Systems and methods for sympathetic cardiopulmonary neuromodulation

ABSTRACT

Methods, devices and systems are described for decreasing the activity of the sympathetic nervous innervation to and from the lungs and the vessels supplying the lungs to treat pulmonary medical conditions such as asthma. In one embodiment, the method may involve advancing an intravascular instrument to a target location in a blood vessel within the intercostal vasculature to ablate either or both the sympathetic afferent and efferent nerves lying within the paravertebral gutter including the visceral fibers that travel to the cardiothoracic cavity and abdominopelvic viscera and the T1 to T4/5 sympathetic chain. In another embodiment, an intravascular instrument may be advanced to the bronchial vessels to ablate either or both the sympathetic afferent and efferent nerves in and around the posterior pulmonary plexus. In one embodiment the ablative agent is a neurolytic agent delivered in a gel. This approach may be utilized to treat other cardiac and pulmonary diseases.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) as anonprovisional application of U.S. Prov. App. No. 62/179,027 filed onApr. 27, 2015, which is hereby incorporated by reference in itsentirety. Furthermore, any and all applications for which a foreign ordomestic priority claim is identified in the Application Data Sheet asfiled with the present application are hereby incorporated by referenceunder 37 CFR 1.57.

BACKGROUND

Field of the Invention

The invention relates in some aspects to systems and methods forsympathetic neuromodulation, including cardiopulmonary sympatheticneuromodulation.

Description of the Related Art

Asthma is a common chronic airway disorder characterized by episodicreversible airflow obstruction, or asthma attacks, that arecharacterized by breathlessness, coughing, wheezing, and chesttightness. Airflow is obstructed by contraction of the smooth musclesurrounding the airway that is thought to be a result of airwayhyperreactivity. Inflammation and increased mucous secretions are alsothought to play a role in exacerbating the asthma attack. Exposures suchas exercise, infection, allergens, chemicals, or airborne irritants maytrigger an asthma attack. At this time, it is not clear how to preventthe development of asthma and there is no known cure. Pharmacologicmethods to control the disease and prevent exacerbations arewell-established and as a result symptomatic treatment has improved overthe past 20 years.

Asthma prevalence is now at its highest level at over 8% of thepopulation in United States. In 2010, an estimated 25.7 million peoplehad asthma: 18.7 million adults aged 18 and over and 7 million childrenaged 0-17 years. As a result of the increasing prevalence of thedisease, asthma has been a focus for public health action. Theprevalence of asthma attacks among persons with asthma, althoughdeclining, remains above 50% and there are an estimated 46.7 millionlost school, work and activity days per year. Asthma visits to theemergency department and hospitalizations were stable from 2001 to 2009but death rates are declining from 2001 to 2009. There are approximately2 million ED visits, 500,000 hospitalizations, and 10 million outpatientvisits for asthma. Each day, this translates to approximately 40,000unscheduled physician office visits, 5,000 emergency room visits, and1,000 hospitalizations due to asthma. Predictors of death due to asthmainclude three or more ED visits in the past year, as asthmahospitalization or ED visit in the past month, overuse of short-actingbeta agonists. There are approximately 4,000 deaths per yearattributable to asthma and deaths occur at a rate of 3.3% per year. Thecare for asthma patients costs over $18 billion of healthcare resourceseach year. As a result of the better medications available to patients,they are living longer but with a higher overall cost to the healthcaresystem since there is no cure for the disease.

Asthma is classified as intermittent, mild persistent, moderatepersistent, and severe persistent. Severe or treatment-resistant asthmais increasingly recognized as a major unmet clinical need. Asthma mayalso be classified as atopic (extrinsic) if symptoms are triggered byallergens (smoke, air pollution, pollen) or non-atopic. Asthma may alsobe classified exercise-induced, occupational or nocturnal. Poorlycontrolled severe asthma, called severe persistent asthma, constitutesabout 5 to 10 percent of asthma patients in United States, orapproximately 1 to 2 million patients. A new procedure has beendeveloped for the treatment of these severe persistent asthmaticpatients, called Alair bronchial thermoplasty. This is a bronchoscopicprocedure in which a minimally-invasive radiofrequency catheter isdelivered through a bronchoscope into the patients airways to directlyablate the smooth muscle lining the bronchi with the goal of reducingthe contractions of these muscles. The procedure typically requires atotal of three separate procedures separated by two to three weeks forup to one hour each under moderate sedation. The FDA approved thetherapy in 2010 based on significant improvements in patients' qualityof life after the procedure. Boston Scientific reported sales of $15-20MM in 2010 and expected $40-50 MM in sales in 2013.

As a result a new treatment for asthma, as well as other diseases, isneeded with the potential of cure. Ideally the treatment would beminimally invasive and require minimal, if any, hospital stay. Theprocedure would, in some cases, avoid direct disruption to bronchialtissue and should not necessitate inserting a bronchoscope directly intothe hyperreactive airways in some embodiments. Ideally, the treatmentcould be performed in one or two outpatient or office visits under alocal anesthetic. This is desirable for both pediatric and adultpatients. The treatment can reduce or eliminate the need for chronicpharmaceutical therapy. Finally, the treatment may preferably be longlasting or permanent. The treatment can result in a significant costreduction to the healthcare system by reducing medication consumption aswell as outpatient, emergency department visits and hospitalizationseach year.

SUMMARY

Disclosed herein are systems and methods for neuromodulating sympatheticnerves of a patient, according to some embodiments of the invention.Some embodiments involve a method that includes inserting a catheterpercutaneously into a first blood vessel; advancing the catheter into asecond blood vessel; penetrating a wall of the second blood vessel witha portion of the catheter, thereby accessing the paravertebral gutter;and neuromodulating sympathetic nerves within the paravertebral gutter.

In some embodiments, the second blood vessel could be, for example, anazygous vein, a hemiazygous vein, an accessory hemiazygous vein, asuperior intercostal vein, an intercostal vein other than the superiorintercostal vein, a costocervical trunk, and a subclavian artery.

Neuromodulation can include delivery of electromagnetic energy, such asRF, microwave, and/or ultrasound energy to a desired anatomic location,such as a portion of the paravertebral gutter, for example. In someembodiments, neuromodulation can include delivering a gel, such as ahydrogel to the paravertebral gutter. The hydrogel could include, forexample, an in situ polymerizing hydrogel, or an injectable hydrogelslurry. The neuromodulation could reduce the signs, symptoms, orotherwise prevent or treat various conditions, including but not limitedto asthma, hypertension, congestive heart failure, coronary arterydisease, arrhythmias including atrial fibrillation, ventriculartachycardia, and ventricular fibrillation, angina pectoris, andpulmonary hypertension.

The sympathetic nerves to be treated can be present at one, two, or morespinal levels, or adjacent ribs (e.g., in the thoracic region). In someembodiments, the nerves reside proximate the C7 or T1 to T4 to T5 spinallevels, or various other levels as disclosed herein.

The neuromodulation could be unilateral or bilateral, e.g., on the leftside, right side, or both, and can be stepwise or within the sameoperative procedure.

Also disclosed herein is a method of modulating sympathetic nerves of apatient, that includes accessing a paravertebral gutter of the patient;and neuromodulating sympathetic nerves within the paravertebral gutter,wherein neuromodulating comprises flowing a gel comprising a therapeuticagent into the paravertebral gutter. The therapeutic agent could includea neurolytic agent, such as, for example, a non-depolarizing agent. Theneurolytic agent could prevents or blocks the release of norepinephrine,and/or be co-administered with a blocking agent. Some examples ofneurolytic agents that can be used include, for example, nifedipine,lamotrigine, minoxidil, reserpine, tetrabenazine, amiodarone,dextromethorphan, valproic acid, mecamylamine, phenoxybenzmine,alfuzosin, haloperidol, desipramine, bretylium tosylate, doxepin,bupropion, taxol, and oxaliplatin. The agent could be combined by ananesthetic, or include ethanol. A gel could have any desired porosity,such as less than about 50 μm, 20 μm, 10 μm, 5 μm, or even less. The gelcould include a biodegradable or bioerodable polymer, or an injectablehydrogel. The gel could include any number of the followingcharacteristics: in situ forming, PEG-NETS, PEG-ester, a PEG hydrogel,shear-thinning, or hyaluronic acid. In some embodiments, the gel has avolume that occupies at least about 50% of the volume of theparavertebral gutter at the levels in which it is delivered to, orcovers substantially the entire paravertebral gutter at the levels inwhich it is delivered to. In some embodiments, the gel has a volume ofbetween about 2 cc and about 30 cc, such as between about 10 cc andabout 20 cc. The gel can be delivered unilaterally or bilaterally, suchas in a rostral or caudal direction, or both. The gel can be flowed atone level (e.g., via one injection site), and flow to a plurality suchas 2, 3, 4, 5, 6, 7, or more levels.

In some embodiments disclosed herein is a method of selectivelymodulating sympathetic nerves of a patient, that includes accessing theparavertebral gutter of the patient; and protecting a first group ofnerves or neurons within the paravertebral gutter from neurolysis,wherein protecting comprises flowing a first hydrogel into theparavertebral gutter in a first direction; and neuromodulating a firstgroup of nerves or neurons within the paravertebral gutter, whereinneuromodulating comprises flowing a second hydrogel into theparavertebral gutter. The first hydrogel can include, for example aneuroprotectant. In some cases, the first hydrogel is released proximatethe first rib toward the inferior cervical ganglion or the region of thestellate ganglion comprising the inferior cervical ganglion. The secondhydrogel can include a neurolytic agent, and be delivered to thethoracic sympathetic ganglia and associated nerves or the thoracicparavertebral gutter.

Also disclosed herein in some embodiments is a system configured forsympathetic neuromodulation. The system can include a catheterconfigured for being positioned percutaneously within a blood vesseldirectly proximate the paravertebral gutter and for delivering atherapeutic agent to the target nerve or target neurons within theparavertebral gutter; and a first hydrogel comprising a neurolyticagent. The system can also include a second hydrogel. The secondhydrogel can include, for example, a blank or neuroprotective hydrogel.The catheter can include, for example, at least one energy deliveryeffector, such as an RF electrode, microwave antenna, ultrasonictransducer, and the like.

Also disclosed herein in some embodiments is a hydrogel for use insympathetic neuromodulation by delivery to the paravertebral gutter of apatient, or other anatomical locations as disclosed herein. The hydrogelcan include, for example, a neurolytic active agent; and a biodegradablepolymer. The hydrogel can have a porosity of less than about 50 μm insome embodiments. The gel could include a biodegradable or bioerodablepolymer, or an injectable hydrogel. The gel could include any number ofthe following characteristics: in situ forming, PEG-NETS, PEG-ester, aPEG hydrogel, shear-thinning, or hyaluronic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates neural anatomy at a single thoracic level.

FIG. 1A is a close-up view of dotted circle 6A of FIG. 1 illustratingvarious structures within the paravertebral gutter.

FIG. 1B is a close-up view of dotted circle 6B of FIG. 1.

FIG. 2A is a horizontal section highlighting various anatomical featuresin the thoracic region.

FIG. 2B is a close-up view of FIG. 2A illustrating selected structuresillustrated in FIG. 2A in or in proximity to the paravertebral gutter.

FIG. 3 illustrates an embodiment of a therapeutic agent delivery systemincluding a catheter that can interface, e.g., removably interface witha syringe or other therapeutic agent housing.

FIG. 4 illustrates a distal portion of the catheter.

FIG. 4A is a cross-section through line A-A of FIG. 4.

FIG. 4B is a cross-section through line B-B of FIG. 4.

FIG. 4C is a cross-section through line C-C of FIG. 4.

FIGS. 5-5C are views of a schematic illustration of a delivery cathetersystem including one or more therapeutic agent housings (e.g., syringes)removably connected to a catheter configured to deliver a plurality oftherapeutic agents into different anatomical locations.

FIGS. 6-6A are schematic illustrations of a delivery catheter systemsimilar to that illustrated in FIG. 5, except the first therapeuticagent housing has only a single chamber fluidly connectable via a firstinput port on the catheter to a first lumen.

FIGS. 7A and 7B illustrate embodiments in which a gel can be flowed intothe paravertebral space.

FIG. 8 illustrates an embodiment of a system and method for sympatheticneuromodulation similar to that described in FIGS. 8A and 8B above, andalso including an energy delivery effector.

FIGS. 9A and 9B illustrate embodiments of target injection sites intothe paravertebral space, focusing on the neural anatomy.

FIG. 10A illustrates one embodiment of possible selected upper thoracicanatomy.

FIG. 10B illustrates some embodiments of distances from the medialmargin of rib head to the medial margin of sympathetic chain.

FIGS. 11A-11C illustrate different anatomical variants in anatomy of theintercostal veins.

FIGS. 12A-12C illustrate the respective anatomy of FIGS. 11A-11C, with acatheter being deployed into the superior intercostal vein.

FIGS. 13A-13C illustrate the respective anatomy of FIGS. 11A-11C,illustrating expansion of an expandable member positioned at the distalend of the catheter against the wall of the vessel.

FIG. 14A illustrates schematically a different view of a catheter withan expandable member at its distal tip within a vessel.

FIG. 14B illustrates schematically the expandable member being expanded.

FIG. 14C illustrates the curved needle sheathed by or otherwiseassociated with the expandable member coming into contact with andextending radially outwardly through the wall of the vessel.

DETAILED DESCRIPTION

Most clinicians agree that a primary cause of asthma attacks is theincreased resistance of air movement through the respiratory tree due toan acute reduction in the lumen of the bronchial/bronchioles andassociated finer air passages. Bronchial/bronchiole narrowing may becaused by bronchospasm of the intrinsic (and possibly hypertrophied)bronchial muscles as well as mucosal swelling. In addition, the attackmay be attributed to the reduction in airway caliber as a result ofedema in smaller bronchioles, bronchorrhea, and excessive bronchialgland secretion. It has also been proposed that these asthmatic airpassageways are in a chronically contracted or reduced state inasthmatic patients and thus it is changes in the bronchial mucousmembrane and secretions that trigger the symptoms of the acute asthmaticattack. Finally, the asthma attack may be propagated as a result of areaction in the pulmonary blood vessels and a resultant decreasedclearance of substances through either the pulmonary blood vessels orthe draining lymphatics.

For treating asthma, curing or substantially improving the patient ofthe underlying bronchoconstriction, inflammation and mucous productioncan be desirable. Curing or substantially reducing the disease of thepatient can result in a significant reduction or resolution of the signsof asthma. Some embodiments of the invention are directed towardsreducing the forced expiratory volume (FEV1) of patients by about 5%,10%, 15%, 20%, or more, reducing patients' rate of exacerbations,improving patients quality of life (e.g., by an improved integratedasthma quality of life questionnaire AQLQ score), increasing thepercentage of symptom-free days (absence of cough, wheezing,breathlessness, sputum during day or night), reducing the number ofpuffs of rescue medication used, percentage of days rescue medicationused, increasing morning peak expiratory flow (amPEF) and pre- andpost-bronchodilator FEV1 and reducing the number of emergency departmentvisits. Persistency of response can also be evaluated. Although the goalof some embodiments of the invention is to cure the patient of asthma,in some embodiments, systems and methods as disclosed herein can treatat least 70% of responders, at least 30% of whom are excellent or goodresponders, or in some cases where 50% are good or excellent respondersand less than 30% who are non-responders. As the therapy is evaluated onmore patients, more appropriate patient selection can allow for higherrates of responders.

Patient selection for the procedure can allow for highest responserates, particularly since severe asthma may not be a single disease asevidenced by the number of clinical presentations and outcomes. Asthmais increasingly being grouped into phenotypes which may evolve intoendotypes—combinations of clinical characteristics and mechanisticpathways. For example, the Severe Asthma Research Program (SARP)identified five groups of adult asthma patients based on lung function,medication use, age at onset and frequency of exacerbations: threegroups of mild, moderate and severe early-onset atopic asthma, a moresevere late-onset obese group of primarily older women with moderateFEV1 reductions and frequent oral corticosteroid use, and a later-onsetbut long duration very severe, less atopic group, with less reversibleairflow limitation. By including sputum eosinophil counts, 4 differentgroups of patients were generated: early onset atopic-asthma, an obesenon-eosinophilic asthma, an early onset symptom predominant-asthma, anda later onset inflammation predominant asthma. In both of these groupingmethodologies, severe asthmatics were distributed among several groups,supporting the heterogeneity of severe asthma. In one embodiment, thelate-onset severe asthma group with high eosinophilic counts can betreated. A SARP study of asthmatic children found 4 clusters:later-onset with normal lung function, early-onset atopic with normallung function, early-onset atopic with mild airflow limitation, andearly-onset with advanced airflow limitation. As genetic and epigeneticdiagnostic approaches to characterizing airway disease are developed,these may aid in the identification of patients that are best suited fora sympathetic neuromodulation approach for the treatment of asthma andother respiratory diseases.

In one embodiment, asthma is treated with a specific focus on asthmathat is triggered by an allergic component. In one embodiment, patientsare selected from a subset of asthmatic patients with severe resistantor severe persistent asthma. In one embodiment, patients are selectedfrom a group of asthmatic patients with atopic asthma. In particular,some embodiments can be appropriate for patients who have severe asthmathat are poor operative risks with marked limitations in cardiopulmonaryreserve.

In one embodiment, the therapy may be delivered to adults above the ageof 18 or adapted for treatment of the pediatric population. Care can betailored based on patient demographics, duration of symptoms, previousand present treatments, number and type of other failed treatments,and/or other factors.

Sympathectomy was developed to help patients suffering fromhyperhidrosis, excessive sweating, almost a century ago. Sympathectomyinvolves the division of adrenergic, cholinergic, and sensory fibers inthe sympathetic trunk. Traditionally, sympathectomy is the totalresection or ablation of the ganglia but the term is also used todescribe the transection of the chain at the level of the rib.Occasionally, sympathectomy is also used to refer to cutting of the rami(white (also gray)) communicantes without division of the chain itself.Similar terms include sympathicotomy, which refers to transection of thesympathetic chain and sympathicolysis, which refers to destruction ofthe chain with a chemical agent. Sympathetic block typically refers tothe placement of removable clips on the chain (thoracic blockade) or theadministration of an anesthetic to the chain.

Sympathectomy was originally performed with a posterior approach thatrequired a longitudinal incision from C7 to T4-T5 and resection of theribs and the transverse process was required. A supraclavicular approachrequiring close proximity to the phrenic, brachial plexus and stellateganglion that resulted in a high rate of adjacent nerve damage.Endoscopic thoracic sympathectomy (ETS) was pioneered in the 1950s andmore broadly adopted in the 1990s as a less invasive approach fortreating hyperhidrosis, facial blushing, Raynaud's disease and reflexsympathetic dystrophy. In this anterior transthoracic procedure, athoracic surgeon makes small incisions between the ribs and inserts anendoscope and a surgical instrument to access the sympathetic chain. Theprocedure offers advantages of superior visualization and lighting formore accurate delineation of anatomy, small incisions, can be performedbilaterally as an outpatient procedure, and does not require single-lungventilation with a double-lumen endotracheal tube. The more commonprocedure involves single-lumen endotracheal intubation and a 5-mmtrocar is inserted into the fourth or fifth interspace in themidaxillary line. The lungs are insufflated with carbon dioxide tocompress lung apex away from the superior sulcus. A second 5-mm trocaris inserted at the base of the axillary hairline, through which acautery device is used to transect the sympathetic chain over theanterior surface of the dorsal rib, sparing the ganglia themselves.

Sympathicotomy is now the most popular method to treat patients in whichthe inter-ganglion fibers are transected. The most recent procedure forsympathectomy is thorascopic video-assisted sympathectomy (VATS) fortreating hyperhidrosis. In this procedure, two 2 mm incisions are madeon each side of what and a small video camera and single dissectinginstrument are passed into the chest. The incisions are so small thatthe procedure is called a “needlescopic surgery.” Like other methods,the sympathetic trunk is directly visualized and divided at theappropriate levels. Nearly all patients are discharged the same day andsuffer only minor discomfort for a few days after the operation. Despitethese minimally invasive treatment options and the safety and efficacyof the procedure, the procedure has not been widely adopted for thetreatment of hyperhidrosis.

Other approaches that have not gained widespread adoption includesingle-port bilateral sympathectomy but this approach resulted in ahigher rate of hemothorax requiring intercostal drainage.

Other approaches include radiofrequency sympathectomy, which has alargely remained the domain of hyperhidrosis.

Selective sympathectomy or ramicotomy has been developed in an attemptto decrease the incidence of compensatory hyperhidrosis (CH) inhyperhidrosis patients. This procedure preserves the sympathetic chainand divides only the rami communicantes, thereby minimizing the damageto the whole sympathetic system. The general consensus is that the rateof severe CS is lower but the technique results in a higher rate ofrecurrence than a conventional transection.

Long-term procedural success rates are on the order of 91 to 98%, themajority of patients requiring only once procedure. Recurrence rates ofhyperhidrosis are on the order of X to 5 percent and incomplete responseis typically attributed to an incomplete transection of the sympatheticchain.

Efficacy of sympathicolytic or chemical approaches to denervating theganglia vary and have largely been applied to lumbar procedures.

Chemical sympathicolysis has also been described using phenol andalcohol (3 ml of 6.5-7% phenol and 3 ml alcohol) or phenol (7%) oralcohol alone (2.5%). In a chemical neurolysis study, n=2/23 patientshad a recurrence of essential hyperhidrosis at a follow up between 8 and18 months. Thus wider adoption of a chemical based-approach has beenhampered by concerns about treatment longevity.

Efficacy of sympathicolysis varies. T2-T3 sympathicolysis with athorascopic procedure resulted in 100% complete and permanent relief intreating palmar hyperhidrosis, 91% significant improvement in axillarhyperhidrosis at 1 year with 52% of patients showing a completedisappearance of hyperhidrosis.

Percutaneous chemical neurolysis has been performed in 23 patients withpalmar hyperhidrosis using CT guidance to the gap of T3-T4 and then alarge volume of injectate travels to the thoracic sympathetic nerve.Palmar hyperhidrosis efficacy was lower than observed with directthorascopic sympathicolysis, curing 19/23 patients, requiring a secondblock with absolute alcohol in 4 patients, and in 2 patients there wasrecurrence at a follow-up between 8 and 18 months.

Chemical blocks are performed using anesthetics (1% lidocaine/30%iohexol, 2.5 ml 0.25% Marcaine with epinephrine for 1-10 days relief,median 4 days).

Some methods to achieve sympathectomy include:

Method of Royle. Open surgical procedure in which all rami are dividedfrom the third thoracic ganglion to the inferior cervical ganglion andthe trunk is severed just below the inferior cervical ganglion and thirdthoracic ganglion.

Method of Adson. Open surgical procedure in which all intervening ramifrom the second thoracic ganglion to just above the inferior cervicalganglion are divided and the trunk is severed above the inferiorcervical ganglion and below the second thoracic ganglion.

Method of Leriche. Open surgical procedure in which the intercostalnerve is retracted upwards and the rami that enter the under surface ofthe nerve are transected. This approach is thought to be suitable onlyfor mild cases.

Method of Levin. A minimally invasive approach in which, at a point 4 cmaway from the spine, preferably in the third or fourth interspace (orT3-T6), a needle is introduced directly to the inferior margin of therib at a 45 degree angle to a depth of about 2 cm. Precautions are takento guard against perforation of the pleura the needle is pushed furthertowards the spine and 2.5 cc of absolute alcohol in injected in a seriesof small spurts. Occasionally the transverse process is bulky andobstructs the desired trajectory of the needle and then the needle isdirected to travel immediately in front of and below the process. Fourinjections, once a week, are given followed by a month's rest, and thenanother series of four injections are administered should any trace ofasthma persist. There is rarely any radical improvement until after thesecond or third injection. Case studies demonstrated completedisappearance of asthma in 100% patients (n=5) with some patientsrequiring only two injections while others required nine. Further workresulted in 72% (13/18 cases) with complete relief.

Modified Method of Levin. At a point about 3 cm from midline a solidcutting needle is introduced down to the lower border of the rib and isdirected 50 degrees forwards, inwards, and downwards until thetransverse process of the corresponding vertebra if felt. The uppermargin of the rib is then followed by the fingertip to a point directlyopposite the level of the process. A strong lumbar puncture needle isintroduced on a slant from below so as to strike the upper margin of therib immediately under the fingertip. The needle is then cautiouslypushed upwards, inwards, and forwards closely hugging the upper marginof the rib for a distance of about 2.5-3 cm. Perforation of the pleuracan be avoided provided the needle is closely applied to the upperboundary of the rib slightly on the posterior plane. The needle is thenrotated to an angle of 90 degrees and the orifice of the needle is nowdirectly behind the thoracic trunk. Assuming the pleura is intact, 1 ccof absolute alcohol is injected and the needle withdrawn. X-ray can beused to confirm the needle position. This procedure can be done for thethird and second interspaces as well as the fourth but the maneuver ismore challenging on account of the greater depth of the ribs. In casestudies 100% of patients (n=3) were free of asthma and in further cases,80% (4/5) obtained complete relief.

Percutaneous ablation is also largely the domain of lumbarsympathectomy. For thoracic approaches, percutaneous injection haverelied on CT images for guidance based on anatomic landmarks. Directvisualization of the ganglia may not be possible using CT. The needlecan be positioned at the tip at the upper joint of the costal headbeside the T3 body and outside of the costal pleura. There is a lot ofcontroversy about which level to denervate to ensure the greatestsuccess with the least risk of compensatory hyperhidrosis. Mostclinicians believe that the extent of compensatory sweating depends onthe level or the extent of sympathectomy. Some physician performedelectrocoagulation between T2 and T3 for palmar hyperhidrosis, T3 and T4for axillary hyperhidrosis, and T2 and T4 for palmar and axillaryhyperhidrosis.

In a 121 palmar hyperhidrosis patient study in which 61 patientsunderwent second rib (R2) transection and 60 patients underwent thirdrib (R3) transection, the failure rate was only 4.1% and there was onlya slightly higher trend towards compensatory hyperhidrosis in the R2group over the R3 group.

In a 141 patient study in which 68 patients underwent T3 and 73 patientsunderwent T4 sympathicotomy, all patients were effectively treated fortheir palmar hyperhidrosis. Improvement was more dramatic in the T3group than the T4 group but the incidence of compensatory sweating andoverly dry hands was lower in the T4 group than the T3 group. Morepatients were very satisfied in the T4 group than T3 but the ‘partially’satisfied rate was comparable between the two groups.

Failure, or recurrence of hyperhidrosis, is largely attributed toincomplete interruption of the sympathetic chain. Nerve regenerationthat occurs 2 to 5 years post-operation is thought to be a late resultof incomplete destruction of the sympathetic chain or sympatheticganglion. Hyperhidrosis recurrence occurs on the order of 0 to 7.6%.Similarly, reoperation rates are on the order of 0 to 3.2% and theseprocedures are typically successful.

If there is reoccurrence of sweating after treatment of IPPH, it isthought to occur within the first two years. Although there have been nolarge controlled studies to compare outcomes between surgicaltransection and resection, late recurrence of hyperhidrosis is thoughtto occur more frequently with a transection rather than a resectionprocedure.

Regeneration in thoracic or lumbar etc. can result in abnormal nervesprouting after injury to the nerves. Sympathetic nerves may formaberrant connections with sensory nerves leading to pain.

Landmarks:

The ribs are an excellent landmark to guide surgeons on the level of theganglia. The neck of the first rib is usually covered by a fat padprotecting the second ganglion. The second thoracic ganglion isconsistently located in the second intercostal space. The third, fourth,and fifth ganglia are not consistently located in the correspondinginterspaces and can be hard to visualize surgically.

Lumbar.

In the lumbar region, sympathetic block can be performed. The procedureis more straightforward because it does not involve the lungs. Typicallyan IV sedative, a local anesthetic is administered, contrast isinjected, and a fluoroscope is used to identify painful areas to correctthe location of the needle tip to assess location. To the inventor'sknowledge, here are no needle based procedures for performingsympathectomy that are currently in use in either the thoracic or lumbarregion.

Lumbar.

In the lumbar spinal cord, a temporary sympathetic block can beperformed with a 19-gauge needle (12-18 cm long) delivering 15 ml of ananesthetic (Marcaine) to L1 or L4-L5. Insertion points are at the levelof junction of 12^(th) rib and erector spinae muscles for L1 and thelevel of line drawn between posterior iliac crests for L4/L5.

Lumbar.

The retroperitoneal surgical technique is performed with an obliqueincision from the lateral edge of the rectus towards the middle of thespace between the ribs and the iliac crest ending at the anterioraxillary line. The lumbar sympathetic chain is located medial to thepsoas muscle overlying the transverse process of the lumbar spine. Onthe left side, it is adjacent and lateral to the aorta and on the rightside it is beneath the edge of the inferior vena cava.

Alternate Celiac—

Celiac plexus block has conventionally been used to guide a celiacplexus block, also the CT-guided anterior approach and the endoscopicultrasound-guided approach. New approach is the ultrasound-guidedanterior approach to celiac plexus neurolysis with median planesingle-needle entry to the preaortic area between the celiac trunk andthe superior mesenteric artery.

Alternate—Paravertebral Block

Anesthetic is injected into the space where spinal nerves emerge fromthe intervertebral foramina. The result is an ipsilateral somatic andsympathetic nerve block of the respective dermatome. A single-sideinjection involving a larger volume (˜15 cm3) at one or moreparavertebral spaces or a multiple site smaller injection (3-4 cm3)volume at multiple levels, usually as many as 6 levels.

A handful of studies were published in the 1930s demonstrating thepotential of dorsal sympathectomy for treating asthma.

In 1935, Levin published his work treating bronchial asthma by dorsalsympathectomy. From Levin's perspective, the sympathetic action isentirely reflex and “from a practical point of view, it matters littlewhether the sensory or motor branch of the reflex arc is severed; inneither case will exciting stimuli provoke a response (Levin 1935).”Levin goes on to provide this rationale that sympathectomy is a suremethod by which to severe all sensory sympathetic stimuli and thus alsodisrupt or eliminate the motor half of the reflex arc. The procedurespecifically denervates bronchial constrictor nerves derived from thesecond to the sixth dorsal rami.

Levin performed alcohol injection on 23 cases and obtained completerelief in 75% of patients with varying degrees of improvement in theremainder of the patients. Cessation of asthma was observed for betweenfour months and over ten years in the patients have been followed.Resistant cases were chiefly those patients with emphysema and collapseof the lung. Perforation of the pleura occurred in 13% (3/23 cases) withno serious consequences. Levin recommends the rami be treatedimmediately below the point of junction with the intercostal nerves andthe trunk divided above the level of the neck of the fourth rib.

Wilensky also concluded that more minimally invasive approaches weremore desirable and resulted in more favorable results than more radicaland invasive procedures such as posterior pulmonary plexus denervation(Wilensky 1940), which denervates the majority of the parasympatheticand sympathetic innervation to the lung. Wilensky performed the Levinprocedure in 18 patients and 78% (14/18) had considerable improvementand, although all patients experience some degree of relief, 22% (4/18)did not have long-term improvement or the improvement was transient. Ofthe 14 patients, 6 were completely cured (43%), 4 were markedly improvedwith a great reduction in number and severity of attacks (29%), and 4had slight relief with less frequent and milder attacks (29%). Somepatients were cured for over four years.

Carr and Chandler performed an open surgical procedure to resect T3 andT4 ganglia bilaterally on 3 patients and T2 to T5 bilaterally on 2patients. All patients demonstrated dramatic clinical improvements intheir asthma symptoms and returned to work. Patients were followed upfor as long as 10 years and improvement was sustained (Carr and Chandler1948).

Abbott also performed single (right or left) and bilateral dorsalpost-ganglionic sympathectomy on 14 patients with promising results: 29%cure (4/14), 64% responders with over 50% reduction in degree of asthma,and 35% no improvement (Abbott, Hopkins et al. 1950). Based onunderlying co-morbidities, Abbott observed that patients that did nothave major associated pulmonary suppuration or destruction had completecure but those with destructive pulmonary suppuration such as emphysemadid not respond as well. Results on a second cohort of patientsreceiving partial or complete pulmonary plexectomy and high rightvagotomy were not improved over the dorsal sympathectomy cohort and werearguably worse (Abbott, Hopkins et al. 1950). Generally, dorsalsympathectomy does not result in any improvement in cough while highvagus resection can be of considerable value. However, dorsalsympathectomy in patients with severe bronchorrhea demonstratedsubstantial reductions in sputum production.

In addition to sympathetic denervation approaches, severalparasympathetic denervation approaches have been developed includingdivision of the right vagus at or below the level of the recurrentlaryngeal nerve ((Abbott, Hopkins et al. 1950; Blades, Beattie et al.1950)). These have then been combined with sympathetic approaches toyield extensive dual sympathetic/parasympathetic denervation: combiningdenervation of the pulmonary plexus (pulmonary plexectomy), dorsalsympathectomy, division of all branches of the vagus to the pulmonaryhilum and lung below the recurrent laryngeal nerve, and stripping of thesheaths around the pulmonary artery and veins (Gay and Reinhoff 1934;Abbott, Hopkins et al. 1950; Blades, Beattie et al. 1950). In fact, someargue that complete sympathectomy is believed to be possible only bytransecting the pulmonary plexus, denuding the main bronchi, and thegreat pulmonary arteries and veins (Dimitrov-Szokodi, Balogh et al.1957). Gobell maintains that bilateral thoracic sympathectomy and vagaltransection yield the best results in asthmatic patients with over 60%cured or improved (referenced in Feinberg, 1935).

Dimitrov-Szokodi demonstrated that by blocking the vagosympatheticpathway in the neck (resection of the branches of the vagus from therecurrent nerve to the pulmonary ligament) and the thoracic sympatheticchain paravertebrally (T2-T5 sympathetic ganglion removal viatransection of the rami communicantes) that it is possible to halt ahistamine-induced asthmatic attack in asthmatics (n=18). The groupobserved for the most part a reduction of mucous membrane inflammationand swelling, reduction of sputum production, reduction in eosinophilia.The group also observed a reduction in asthmatic signs, an indirectimprovement in emphysema and a reduction in bronchospasm. On average,patients have an increase in vital capacity of about 18% and rise of 16%in average pulmonary ventilation rate. Finally, the heavy and frequentasthma attacks accompanying the condition had either stopped (10/18,very good) or were considerably reduced (7/18, good).

In summary, clinical data suggests that interruption of either thesympathetic or parasympathetic arms produces comparable results in therelief of asthma even though they are thought to have antagonistic motoreffects, supporting the theory of a reflex arc. Interruption of thesympathetic or the vagus is sometimes curative, frequently beneficialand sometimes ineffective. Roughly 50 to 70% of patients are definitelyimproved while the 30 to 50%, after temporary improvement, are in nobetter condition than before the operation. The approximate 30-40% ofpatients who have been cured have been followed for 2 years or more.

Finally, patients whom fail a parasympathetic or sympathetic procedurethat go on to have the other arm of the autonomic system denervated havethe most disappointing results. This is likely because a neurogenicmechanism does not play a role in these patients and therefore they willnot obtain relief from operation on any extrinsic neural pathways.

Newer Studies.

More recent studies evaluating pulmonary function after sympathectomyfor the treatment of hyperhidrosis in patients with no lung disease havefound no or only mild changes in pulmonary function and mild increasesin airway resistance, small decreases in heart rate with preserved leftventricular function and ejection fractions, and also preserved exercisetolerance.

Gonzalez et al (2005) evaluated pulmonary function in 37 patientsundergoing sympathectomy for primary hyperhidrosis. Patients withotherwise normal lung function demonstrated a 5.2% decrease in forcedvital capacity (FVC), FEV1 and the forced expiratory flow (FEF) between25 and 75% of vital capacity was decreased by 5.1% (Ponce Gonzalez,Serda et al. 2005). There were no differences in peak expiratory flow(PEF), however, and all patients remained asymptomatic. Three patientswho were positive on methacholine challenge prior to surgery but 6patients were positive after the procedure (not statisticallysignificant). After 12 months, the forced vital capacity started torecover (+1.5%) but forced expiratory volume (FEV1) and FEF showedsustained reductions. The authors conclude that sympathectomy results ina mild impairment in bronchomotor tone with no clinical consequences.

Two patients in this series had asthma that were in stable condition andhad a positive methacholine challenge test at baseline and after theprocedure but the provocative methacholine concentration (PC20) was nothigher. Furthermore, during follow-up, they experienced neitherparticular respiratory symptoms nor the need for rescue bronchodilatorssuggesting that their condition had not worsened (Ponce Gonzalez, Serdaet al. 2005).

Ben-Dov reported no or mild effects on lung function aftersympathectomy.

In a more recent study, Fredman and colleagues report worsening ofasthma in some patients after thoracic sympathectomy. In their series of626 patients, 14 of their patients experienced asthma beforesympathectomy (Fredman, Zohar et al. 2000). After sympathectomy, 5reported no change in the frequency or severity of their asthma, 1described an improvement in their symptoms, and 8 reported a worseningof their asthma symptoms. In this subset of patients, 57% described anincrease in the number and severity of asthma attacks. However, theseadverse symptoms were not cited by the patients who regretted havingundergone the procedure. Adar and colleagues reported non-specific mildrespiratory complaints in 20% (18/93) patients that were followed up ataround 18 months after the removal of T2/T3 ganglia for the treatment ofplantar/palmar hyperhidrosis (Adar, Kurchin et al. 1977). In addition,in 2 patients there was a re-exacerbation of childhood bronchial asthmaand in one patient there was reported cessation of attacks of asthmaafter the operation. This was a supraclavicular approach that alsorequires retraction of the phrenic nerve and so some of the side effectsmay be related to the invasiveness of this surgical approach.

There has been a resurgence of interest in recent years in the use ofparavertebral blocks with anesthetics to temporarily alleviate painafter thoracic or thoracoabdominal surgery. These blocks are used forthoracic procedures including breast surgery, rib fractures,video-assisted thoracic surgery (VATS) and minimally invasive cardiacsurgery. Depending on the extent of the surgery, paravertebral blockscan be a unilateral single needle-injection to a bilateral continuouscatheter-delivered block. Unilateral thoracic paravertebral blocks(TPVB) can be performed to temporarily achieve anesthesia and analgesiawhen the afferent pain (somatic, sympathetic) input is predominantlyfrom the unilateral chest, such as fractured ribs. Bilateral TPVB havealso been used perioperatively during thoracic, video-assistedthoracoscopic surgery, appendectomy, cholecystectomy and breastsurgeries to achieve postoperative analgesia. This can be achieved bydelivering local anesthetic to the region to achieve ipsilateral somaticand sympathetic nerve blockade in multiple contiguous thoracicdermatomes above and below the site of injection. The technique isconsidered simple and easy to learn and safer and easier than a thoracicepidural. It is safe to perform in sedated and ventilated patients anddoes not require palpation of the ribs. There is a low incidence ofcomplications.

An example of the different levels that the block can be performeddepending on the target organ is provided below:

TABLE 1 Thoracic paravertebral levels to deliver therapy treatconditions affecting a given target tissue. Continuous ParavertebralSingle Target Tissue Block Paravertebral Block Breast T1-T2 T2-T6Esophagus/Stomach T2-T3, bilateral Lungs/Thorax T4-T5 (classic) or T5-T6(intercostal) Liver T6-T7, bilateral Abdomen T8-T9, bilateral Pelvis(rectum, uterus, T11-T12, bilateral T10-L1 prostate)

The purpose of these blocks is to temporarily block nerve conduction inthe afferent fibers conveying pain signals as can be measured with thehalt of somatosensory evoked potentials (SEPs).

In the paravertebral block approach, approximately 5 to 10 ml ofanesthetic (1%) or analgesic (0.5%) is slowly injected. Motor blockadeoutside of the surgical dermatomes is minimal with an anesthetic.Failure rates associated with paravertebral blocks is published on theorder of 6-10% and is thought to reflect the challenge in defining theparavertebral space. Compared to the epidural block, the paravertebralanesthetic block infrequently results in hypotension, does not carry therisk of postoperative nausea and vomiting, urinary retention, orpruritus. Also, it does not carry the risk of respiratory depression andthe preservation of forced vital capacity after thoracotomy is improved(75% vs 55%).

Complications of these approaches include pleural puncture (around 1%),pneumothorax (0.5%), hematoma (2.4%), vascular puncture (3.8-5%),epidural or intrathecal spread. Pneumothorax is the most dreadedcomplication of the procedure in the ambulatory setting and is morelikely to occur between T1 to T8 than T10 to L3. Epidural spreadtypically results in transient hypotension and bilateral lower limbweakness (˜5%). Epidural spread can be avoided by taking a perpendicularapproach to the skin as the spinous process is approach as opposed to amore lateral/medial angle and reducing the anesthetic administered toless than 15 ml. For example, by administering 5 ml of anesthetic inmultiple levels, administering 5 ml of anesthetic followed by 10 ml ofanesthetic at a later time, this complication can be avoided. Duralpuncture and subsequent intrathecal needle placement and anestheticinjection is more problematic, particularly at T4 or higher, as patientsmost patients will require intubation or artificial ventilation untilthe effects of the injectate dissipate. These complications may bedramatically reduced with the use of ultrasound guidance and slowlydelivering the anesthetic. One report found that 4 to 10% of patientshave clinical significant parasympathetic discharge at needle placementresulting in hypotension, bradycardia and near syncope. To giveperspective though, these complications are comparable to or less thanthe levels with other blocks such as epidural, intrapleural, orintercostal blocks.

These percutaneous approaches can be adapted to deliver agents ortherapy to the sympathetic chain and rami to treat asthma and otherpulmonary or cardiac conditions. More specifically, the directpercutaneous needle or catheter access to this space and can be used todeliver neuroablative agents or neuroablative therapy to theparavertebral space and specifically to the sympathetic afferents and/orefferents.

In one embodiment, the patient is placed in a seated position oralternately in a lateral position. Ideally, the treatment should beperformed in an area with adequate monitoring and resuscitationequipment. The procedure can be performed with or without sedation. Ifsedation is needed, in one embodiment a combination of midazolam andfentanyl can be given to the patient and re-administered as necessary.The injection site is disinfected with chlorhexidine and anesthetizedwith 1% lidocaine delivered with a 25 gauge safety needle (3.75 cm).Typically, an 18- to 22-gauge Tuohy needle is employed to perform theprocedure. A 25-gauge spinal needle may be used initially as atransverse process ‘finder’ needle.

In one method, the needle is inserted 3 to 4 cm lateral to midlinealigned with the caudal end of the spinous process. The needle isadvanced at a 90 degree angle to the skin in all planes to strike thetransverse process or the head of the rib at a depth of about 2.5 to 3cm. Following contact with the transverse process, the needle is walkedoff the lamina and advanced 1 to 2 cm in the angle of entry to thecoronal plane either at the level above or below it. The angle is not toexceed 90 degrees to the coronal plane to avoid pneumothorax. The needlecan be advanced with or without redirecting medially for 1 to 2 cm, asneeded, or until the vertebral body is contacted.

Another approach involves inserting a needle 1 cm from midline at thelevel of the intervertebral foramen and advancing the needle in aperpendicular plane until it contacts the lamina. The needle is thenwalked off the lateral edge of the lamina and advanced 1 cm to deliverthe anesthetic.

Yet another modification is inserting the needle perpendicular to theskin to contact the posterior transverse process. The needle is thenwithdrawn to the skin and redirected beyond the transverse process at a15 to 60 degree angle to deliver the needle below the transverseprocess. A loss of resistance may be felt as the costotransverseligament is pierced.

Yet another modification to the approach is to insert the needle 2.5 cmfrom midline at the level of the intervertebral foramen and walk it offthe lamina and then advancing it 1.5 cm deeper at a 45 degree angle tothe skin.

In yet another embodiment, the needle is advanced in-plane between 2transverse processes and positioned past the costotransverse intercostalligament and posterior to the parietal pleura before 5 to 10 ml ofanesthetic is delivered slowly. If the anesthetic is delivered in theright place, the pleura will be pushed anteriorly.

Approximately 5 to 10 ml of neuroablative agent are slowly injectedafter negative aspiration for blood. Also, a ‘drop technique’ may beemployed, in which a drop of ropivacaine is placed on the top of theneedle and the patient is asked to breathe deeply. If the ropivacainedrop follows the breathing pattern, the needle is through to beintrapleural/in the lung. If the ropivacaine drop is not affected by thebreathing pattern and no blood is aspirated, the needle is connected toa tubing to allow for the slow injection of 5 ml of anesthetic with a 10ml syringe. The injection should not offer a lot of resistance. If theblock is continuous, a 22-gauge catheter can be introduces into theparavertebral space, typically 3 to 4 cm beyond the tip of the needle,and the needle withdrawn.

In this approach, multilevel paravertebral block or ablation can beachieved by introducing the needle or catheter at the thoracic third orfourth level and injecting approximately 10 ml of the agent.

In one embodiment, the delivery of 15 to 20 ml of a neuroablative agentto one level is as effective at achieving multi-level ablation asinjecting 5 ml each in multiple adjacent injections. If a wide block isdesired, however, it may be preferably to do multiple injections or 2injections several dermatomes apart.

An intercostal approach takes advantage of the continuity between theintercostal and paravertebral spaces to deliver a neuroablative agent ortherapy from an adjacent site. Using this technique, the segment to betreated is targeted via the corresponding intercostal space. Thisapproach is more superficial and may be safer than the classicparavertebral access approach. This approach may have a lower risk ofpneumothorax, hematoma, infection, neuraxial blockade, or vasovagalresponse. Thoracoscopic blocks using this approach are typically placedat level T5 or T6.

In one embodiment, a 5 cm, 18 G Tuohy (introducer) needle is inserted ata point 8 cm lateral to the midline and advanced into the intercostalspace to make contact with the rib. When the contact is established, theneedle is reoriented 45 degree angle rostral and 60 degrees medial tothe sagittal plane to contact the lower third of the rib. The needle isthen walked off the inferior border of the rib at the same orientationwith the bevel oriented medially and advanced an additional 3 to 10 mm,more preferably 3 to 6 mm, under the rib to lie in the subcostal groove.After the slow injection of about 5 ml of anesthetic (ropivacaine,0.5%), a 20 to 22 gauge catheter is advanced medially in the intercostalspace through the needle toward the paravertebral space. In thisapproach, the needle orientation reduces the risk of pleural puncture.The catheter is advanced about 8 cm from the site of introduction of theneedle and the introducer needle is removed. After the catheter issecured in place, an additional 10 ml of neuroablative agent is injectedslowly after confirming negative aspiration of blood.

As with other approaches, one injection or one continuous delivery canprovide multiple levels of paravertebral blockade. Injection of 10 ml ofcontrast or chemical agent through the intercostal catheter results inboth extrapleural and paravertebral spread over multiple levels,typically 2 levels rostrally and 3 levels caudal to the catheter tip.

In the case of single injection, between 1 and 20 ml, more preferably 3to 10 ml, more preferably 5 ml may be delivered to the paravertebralspace. In the case of continuous delivery, an agent may be delivered at7 to 10 ml/hour, more preferably 7 ml/hour, although bolus dosing of 3-5ml may be employed as necessary to reach a particular adjacentdermatome.

In another embodiment, a single dose of anesthetic is delivered firstprior to delivery of the neurolytic agent, to confirm appropriateplacement of the chemical agent. Similarly, a single dose of anestheticcan be co-delivered with contrast agent.

In one embodiment, this approach is developed and the chemical agent isadministered over a period of several days, most preferably severaldays, in order to achieve complete disruption of the sympathetic chain.

In another embodiment, contrast can be delivered to the site to confirmthe spread of the injectate. A period of time, between 5 and 15 minutes,allows for the diffusion or clearance of the injectate from the site. Atthis point, 5 to 15 ml of neuroablative agent is delivered to the sameregion as the contrast.

Alternatively, contrast can be mixed with neuroablative agent and thespread of the agent can be confirmed intraprocedurally.

Injection of a neuroablative agent into this space will diffuse freelythrough the retropleural space, bathing the spinal nerves, thesympathetic trunk and its rami and the cardiac nerves which runanteriorly into the posterior mediastinum (T1 to T4).

While diffusion of a liquid or chemical agent through the rib and theposterior intercostal membrane is not possible, injected solutionreadily spreads around the internal aspect of the rib and through theinternal intercostal muscle to gain access the subpleural space. Fromhere, the injectate passes between the ribs and the pleura to theadjacent intercostal spaces by passing through the flimsy fibers of theinternal intercostal muscle. Volumes of 3 ml or more will spreadmedially in the fascial planes to enter the paravertebral space andsurround the sympathetic chain and have been used to achieve pain reliefafter cholecystectomy. Thus, in one embodiment 3 to 5 ml of aneuroablative agent injected at a point 7 cm from midline atapproximately 3 mm beyond the lower edge of the rib. The injectate willtravel within the intercostal space and may continue on to paravertebralspace to surround the sympathetic chain. Depending on the volume anddirection of the injectate, one injection or administration of therapymay be targeted to multiple adjacent intercostal and or paravertebrallevels. An advantage of injecting at this lateral location is that thedistance from the lower edge of the rib to the pleura is about 8 mm,leaving space for the needle. In another embodiment, more controlleddestruction of the nerves can be desired. In this case, multiplebilateral levels can be injected with smaller volumes of neuroablativeagent to achieve the same therapeutic effect.

In another approach, a posterior intercostal nerve block approach can beadapted to take advantage of the continuity between the intercostal andparavertebral spaces. In one embodiment, the neuroablative agent ortherapy is injected or delivered, respectively, directly into oneintercostal space to provide therapy to several adjacent dermatomes.Provided sufficient volume of an agent is delivered, the neuroablativeagent may travel medially through the intercostal to the paravertebralspace where it then spreads to longitudinally within the paravertebralgutter to multiple dermatomes. Care should be taken to avoid subpleuralspread with this technique.

In another embodiment, a needle or catheter can be advanced into theextrapleural space between the pleural and the intercostal muscles and apocket or potential space created full of neuroablative agent. Thepocket can be a single level or extend over multiple rib levels.

In another embodiment, the catheter is directed into the subcostalgroove and neuroablative agent is delivered entirely within oneintercostal space. In yet another embodiment, the catheter is directedmedially into the intercostal space itself, and neuroablative agent isdelivered over three to 5 intercostal spaces.

In yet another embodiment, a catheter can be extended up theparavertebral gutter for two to four or five levels.

A modification of this technique is also described in which a patient issits upright and the skin is pierced in the same transverse plane as themost caudal tip of the spinous process. A skin wheal is made at adistance of 3-4 cm lateral to the midline in the thoracic region. Thesurrounding paraspinal muscles are then infiltrated with localanesthetic as well. A 22 gauge 9 cm spinal needle is inserted throughthe wheel and the stylet removed. A 10-ml syringe containing 0.5%lidocaine is attached to the hub of the spinal needle and the needle isadvanced to the vertebral lamina maintain a 45 degree angle to thecoronal plane with medical direction. By starting at a 45 degree angleand gradually increasing it to no more than the perpendicular, thetechnique assures that at no time the needle is directed towards thepleura. In average sized patients this translates to a depth of 5 to 6cm and somewhat less in women. Once the lamina is contacted by thesyringe and aspirated for blood or cerebrospinal fluid, a small volumeof anesthetic is delivered into the periosteum to provide furtheranesthesia for the block. Then a hemostat to be used as a depth markeris placed on the needle at a distance of 1 to 1.5 cm from the skin whilethe needle remains in contact with the lamina. Holding the hemostat inone hand and the syringe in the other, the spinal needle is withdrawnalmost to the skin, redirected slightly laterally and readvanced in thesame transverse plane with a greater angle to the coronal plane. This iscontinued until the needle is walked laterally off of the lamina and isable to be advanced to a depth at which the hemostat is in contact withthe skin. Following negative aspiration of air, blood, or CSF, a 3 mltest does of lidocaine is injected. Three minutes later, the remainderof the dose of anesthetic can be slowly injected. Typically, a total of4-5 ml are injected per spinal segment. Keeping the patients upright for10 minutes can enhance the longitudinal spread. Depending on the volumeof anesthetic used, block could be achieved anywhere from two to tenspinal segments. This method results in anesthetic deposited around thedural sleeve (peridural) as well as paravertebral space. As a result,sensory and sympathetic (and motor) block is achieved.

These blocks have also been performed using phenol neurolysis for cancerpain. Intrathecal injection is rarely observed (0.52%) as is transienthypertension (4.6%) and bilateral sensory blockade (1.3%), althoughthere were no permanent sequelae.

Multi-level sensory blockade can be achieved up to 93%.

This approach is also used to treat reflex sympathetic dystrophy by someauthors.

Approaches to confirm needle location include loss of resistance,pressure drop, neurostimulation, and ultrasound guidance are alsodisclosed.

Loss of resistance techniques can be used to confirm entry into theparavertebral space and are performed with an 18 gauge or lower Tuohyneedle and a loss-of-resistance syringe filled with saline or air. Theneedle is simply advanced until the resistance is lost, indicating thatthe superior costotransverse ligament has been traversed.

The pressure transducer approach involves connecting a 18-gauge Tuohyneedle to a pressure transducer via pressure tubing. When the needleenters the paravertebral space, the pressure drops but the needle shouldbe advanced very carefully.

The neurostimulation technique involves using an insulated 18-gauge or22-gauge Tuohy needle connected to a nerve stimulator delivering acurrent of 2.5 to 5.0 mA with a pulse duration of 0.1 milliseconds and afrequency of 2 Hz. When the needle is near the nerve bundle, a motorresponse is elicited as evidenced by the intercostal or abdominalmuscles. The intensity of contraction is generally recognized to berelated to the distance between the needle and the intercostal nerve.The ideal position of the needle is when the muscle response ismaintained with a current less than 0.5 mA.

A low frequency ultrasound probe can be connected to an ultrasoundmachine (e.g. S-Nerve, Sonosite) parallel to the spinous process. Thescan improves guidance during the ‘classic’ posterior paravertebralapproach by providing identification of the transverse process, thecostotransverse intercostalis ligament, the pleura, and the lungdynamically. Asking the patient to breath during this approach helps tofacilitate the scanning. Similarly, ultrasound assists in theintercostal approach to the paravertebral space (10 to 15 MHz probe) byproviding identification of the ribs and the pleura. As with the formerapproach, asking the patient to breath during imaging assists invisualizing lung movement. By rotating the probe over the long axis ofthe rib and tilting it, the external intercostal muscle and internalintercostal membrane can be identified, allowing placement of the needlebetween the internal intercostal membrane and the parietal pleura.

A variety of similar anesthetic block techniques can also be adapted forthis purpose including: continuous intercostal nerve block, extrapleuralintercostal nerve block, extrapleural paravertebral block, retropleuralanalgesia.

A multi-level (dermatome) paravertebral block can be achieved asfollowed. An 18-gauge Tuohy needle is inserted perpendicularly into theskin at the level of the T6-T7 interspace, 2.5 cm laterally to the tipof the spinous process, then further until the transverse process wasreached. The needle is then slightly withdrawn and redirected rostrallyat a 45 degree angle to the skin for up to 1.5 cm deeper than the depthof the bone contact. The catheter is then inserted through the needle 1to 2 cm beyond its trip.

22-gauge Quincke spinal needles, 22-gauge blunt nerve block needles(Epimed Intl), 20 gauge radiofrequency blunt needles (Cosman Medical)can be utilized in some embodiments.

If a minimally invasive, endoscopic, or thoracoscopic procedure isdesired, there are several approaches to transecting or ablating thenerves within the paravertebral foramen. In addition to cervicothoracicganglionectomy at the desired levels and division of the ramicommunicantes, the following transection points can be done to reducethe likelihood of regeneration:

-   -   1) Transect lateral to the posterior root ganglion,    -   2) Transect the anterior and posterior root separately at a        point just medial to the posterior root ganglion (extraspinal        root section)    -   3) Transect the posterior root at a point just medial to the        posterior root ganglion and then transect the anterior root more        medially within the arachnoid    -   4) Transect the communicating rami through clipping or dividing.    -   5) Transection of the anterior root intraspinally.

If deemed necessary, a biocompatible suture or cuff or cylinder may besecured around the nerve stump to provide additional protection againstnerve regeneration.

Access can be achieved with a 14/1000 guide wire through a commerciallyavailable 6-12 French steerable sheath.

The development of minimally invasive or percutaneous approaches toperforming sympathectomy has been hampered by concerns about inadvertentdamage to the intervertebral artery or veins. Hemothorax requiringpleural drainage occurs on the order of 2.5% in surgical thoracicsympathectomy procedures for the treatment of palmar hyperhidrosis.Accidental dissection of an intercostal vein can result in 300 to 600 mlblood loss during dissection of the sympathetic chain. Thoracoscopicprocedures are careful to avoid dissection of the arteries and veins inthe region, particularly on the right side as significant bleeding canresult. Inadvertent damage and thus troublesome bleeding occurs morefrequently when the vessels run anterior to the sympathetic chain.

Neural Circuits

Clinical research suggests that neural control of the heart and lung isabnormal and that neurogenic mechanisms may contribute to thepathogenesis and pathophysiology of acute and chronic cardiopulmonarydisease. The maladaptive neural responses to disease are thought tooriginate from one or more of the: 1) parasympathetic afferent and/orefferent arm, 2) the sympathetic afferent and/or efferent arm, 3)‘intrinsic’ peripheral neural circuits that lie within or just externalto the lung or heart, 4) neural circuits between the lung and heart, 4)the central nervous system (CNS), and 5) the somatic nervous system.

Parasympathetic. There is general agreement that vagal efferent fibersprimarily control airway smooth muscle tone (bronchoconstriction) andpossibly mucus secretion. Vagal afferent fibers carry information ontracheobronchial pain and mediate the cough reflex. The vagal efferentfibers may become hypersensitized and trigger cholinergic reflexbronchoconstriction upon stimulation of sensory receptors in the airwaysby inflammatory mediators like histamine, bradykinin, and prostaglandin.Sympathetic arm control. The role of sympathetic efferent fibers andsympathetic sensory afferent fibers (or spinal cord-derived sensoryfibers) in the initiation and persistence of asthma is poorlyunderstood. Several studies and theories support for sympathectomy inthe treatment of asthma since it may 1) disrupt the reflex spasm of thepulmonary veins allowing asthmogenic substances that have been trappedin the lung capillaries to be more effectively cleared from the lungs(Feinberg 1935) 2) resensitize the chronically constricted bronchialmucosa and pulmonary blood vessels to epinephrine and norepinephrine andother blood-born mediators, which exert a local effect in the lung byshrinking bronchial mucosal membranes and reducing secretions (Freeman,Smithwick et al. 1934; Balogh, Dimitrov-Szokodi et al. 1957) 3) overcomevagotonia, 4) neurolysis of the thoracic sympathetic ganglia and ramiwith absolute alcohol injections results in a cure or dramaticimprovement in asthma in 75% of severe intractable asthma cases (Levin1935). Excitatory non-adrenergic non-cholinergic neurons (eNANC). eNANCneurons may play a major role in neurogenic inflammation resulting in 1)increased afferent innervation in bronchi and vessels 2) increasedsensitivity to substance P (SP) and neurokinin A (NKA) resulting inenhanced maximal contractile smooth muscle cell force in response toallergens, 2) hyperreactivity/hyperalgesia of airway sensory nerveendings, possibly due to epithelial shedding and exposure of these nerveterminals to mediators such as bradykinin; prostaglandins and cytokines;3) Upregulation of sensory neuropeptide effects in asthmatic airwayseither through increased peptide production, increased NK1/NK2 receptorexpression, or reduced peptide degradation. These neurons may travelwith the parasympathetic and/or sympathetic system. Since asthmaticsubjects have rapid and exaggerated bronchoconstrictor responses to awide variety of stimuli, bronchial hyperreactivity may be triggered by apreponderance of excitatory (cholinergic and eNANC), a deficiency ofinhibitory (α-adrenergic receptors, reduced β-adrenergic receptors,iNANC) control, increased inflammation (mast cells) or due to amaladaption in the capacity for catecholamine clearance and or reuptake(norepinephrine reuptake transporter (NET)). A related hyperreactivityor hypersensitivity has been observed in the heart.

Some embodiments can modulate the activity of these hypersensitivefeedback loops in order to restore function, possibly through theprocess of recalibrating or desensitizing the neural feedback or throughdeliberately the hypersensitizing an aberrant hyposensitive arm.Generally, then, therapy may be directed at modulating the extrinsiccircuits from the heart and the lungs such as those within thesympathetic afferent—CNS—efferent feedback loop, the parasympatheticafferent—CNS—efferent feedback loop, or broadly from, for example,sympathetic afferents to the CNS to parasympathetic efferents or viceversa. In another embodiment, therapy may be directed at intrinsiccircuits within the organs, such as between the anterior and posteriorpulmonary plexuses or the intrinsic cardiac ganglionated plexuses orsuperficial and deep cardiac plexuses. In another embodiment, therapymay be directed towards extra-CNS feedback loops such thecardiopulmonary neural circuits, such as those fibers that run betweenthe superficial and deep cardiac plexuses and the anterior and posteriorpulmonary plexuses. In another embodiment, therapy may be directedtowards aberrant extra-CNS feedback loops that form in response toischemia or other damage to the nervous system. These aberrantconnections may form between the autonomic and somatic nervous system orwithin the autonomic nervous system. In some embodiments, therapy isdirected towards aberrant connections between the parasympathetic andsympathetic nervous system, the sympathetic nervous system and theafferent visceral/somatic nervous system.

Some embodiments relate to modulating the maladaptive neural responsesthat contribute to or are a result of lung or cardiac disease bydisrupting the intrinsic and/or extrinsic neural reflex arcs of theseorgans. Interruption of these reflex arcs may result in a resetting orrebalancing of the autonomic nervous system and thus act as aphysiologically adaptive response to the disease. The intrinsic reflexarc within the lung, mediating bronchospasm, containing the sympathetic,parasympathetic, somatic fibers and interneurons (e.g. intrapulmonaryganglion) may be targeted with the therapy, including but not limited tothe posterior and/or anterior plexus. Alternatively, the extrinsicreflex arcs between the lungs and the heart, such as the cardiopulmonaryreflex arc, may be targeted with the therapy. In another embodiment, theintracardiac ganglia are targeted to modulating the intrapulmonaryganglia, and vice versa. Alternatively, aberrant extra-CNS reflex arcsthat form may be targeted, for example the aberrant connections thathave been demonstrated between sympathetic efferent fibers and thedorsal root ganglia, or vice versa. In another embodiment, theparasympathetic-sympathetic reflex arc is disrupted in the regionoutside the CNS and outside of the organs, as the nerves exit the spinalcord or brain and course towards the organs. In some embodiments, thenerves lying in the paravertebral gutter and/or intervertebral foramenare modulated, including afferent and efferent nerves. In anotherembodiment, the afferent nerves carried in the vagus are modulated todisrupt the functional antagonism between the efferent sympathetic andparasympathetic nerves. In yet another embodiment, the afferent nervescarried in the sympathetic nerves are targeted and modulated to achievethe same effect. In some embodiments, the therapy is targeted atreducing the activity of the thoracic sympathetic afferent and/orefferent nerves. In one embodiment, the therapy is targeted to decreasethe activity of the sympathetic afferent nerves innervating the heartand lung to disrupt the pro-inflammatory cascade that results in‘neurogenic inflammation’ causing bronchoconstriction, vasodilation,inflammation, vascular hyperpermeability, cough, and mucous productionin the lung, and angina, vasoconstriction, vasospasm, ischemia, atrialarrhythmias, ventricular arrhythmias, fibrillation, bradycardia ortachycardia, and myocardial infarction in the lung.

The sympathetic chain (or sympathetic trunk) is a bilateralparavertebral structure that runs posteriorly in the neck and posteriorchest down to the level of the second lumbar vertebra. Along the lengthof the chain are sympathetic ganglia or cell bodies of the sympatheticpost-ganglionic nerves (or paravertebral ganglia). Typically, thecervical sympathetic chain includes three ganglia, the superiorcervical, the middle cervical, and the inferior cervical ganglia,although additional middle or intermediate ganglia have been observed.Continuous with the cervical ganglia are ten or eleven thoracicsympathetic ganglia. Frequently, the first thoracic ganglia is fusedwith the inferior cervical ganglia to form the stellate(cervicothoracic) ganglion which typically lies transversely andmedially over the head of the first rib, at the level of C7, anterior tothe transverse process of C7, superior to the neck of the first rib, andjust below the subclavian artery. The chain courses through a potentialspace called the paravertebral gutter, discussed elsewhere.

The upper thoracic sympathetic chain is located behind the pleura andover the head and neck of the ribs, close to the articulation with thevertebra. The ganglia are typically located directly in front of thecorresponding rib at the level of each thoracic nerve. The chain ascendsvertically to supply each nerve root with an afferent and an efferentbranch. White and grey rami communicans are the means by which theganglia interact with the spinal nerves. The grey rami communicans arepresent in all segments and largely contain efferent postganglionicsympathetic fibers. The white rami communicans contain afferent andpreganglionic fibers that run from T1 to L2 segments. The cervicalconnection to the spinal cord is thought to be through the white ramicommunicans of the upper thoracic nerves (Cunningham 1913). For example,the stellate ganglion receives a white communicating ramus from thefirst thoracic nerve and gives grey communicating rami to the eighthcervical nerve and the first thoracic nerve. The sympathetic chain andthe white and grey rami communicans lie within the paravertebral gutterand thus therapies directed towards these targets can be delivered inthe paravertebral gutter.

Preganglionic sympathetic nerves exit the spinal cord in the ventralroot of the spinal nerve and pass into the corresponding sympatheticganglion. These neurons may take several paths upon entering theganglion: 1) synapsing with a post-ganglionic neuron within the samelevel of the sympathetic chain, 2) traveling up the sympathetic chain tosynapse with a post-ganglionic neuron at a cervical or higher thoraciclevel, or 3) traveling down the sympathetic chain to synapse with apost-ganglionic neuron at a lower thoracic level. From there, thepost-ganglionic neurons may travel to innervate the periphery by way ofa) the gray communicating rami to the anterior/ventral, dorsal/posterioror other communicating rami, or b) passing up or down the sympatheticchain to exit the sympathetic chain before exiting to innervate theperiphery (pre-ganglionic). The pre-ganglionic sympathetic efferentneurons release acetylcholine as their primary excitatoryneurotransmitter onto the post-ganglionic sympathetic neurons.

Of relevance to sympathetic visceral targets, additional nervefibers/rami containing efferent and afferent visceral sympathetic fiberscourse directly out from the sympathetic chain to the visceralstructures. These nerve bundles can be barely visible threads or finefiber bundles and often multiple nerve bundles can be observed exitingthe sympathetic chain towards the viscera. At the level of the upperthoracic chain, these post-ganglionic fibers do not have distinct names,likely owing to their size and variability. In these cervical chain,these are referred to as the inferior, middle, and superior cardiacnerve (although these nerves also carry pulmonary fibers). In the lowerthoracic chain, these fibers are called splanchnic nerves and contain amixture of pre-ganglionic and post-ganglionic fibers traveling towardsprevertebral ganglia and post-ganglionic fibers.

Of relevance to sympathetic cutaneous targets an estimated seven to ninerami emanate from each ganglia and many proceed posterolaterally to jointhe under surface of the intercostal nerve in the space immediatelyabove (Levin 1935). These communicating branches may be myelinated orunmyelinated. The rami may also provide fibers to the visceral organseither directly or after they have joined the ventral ramus of thespinal nerve or intercostal nerve. Although the intercostal nerves areconventionally though to supply the thoracic wall, Levin believed thatall of the dorsal sensory afferent sympathetic pulmonary fibers arecontained in the communicating rami passing to the intercostal nerves,whether excitatory or inhibitory (Levin 1935). These fibers can also betargeted by delivering therapies to the paravertebral gutter.

Sensory (afferent) fibers enter through either the anterior/ventral (inlargest numbers), dorsal/posterior or other communicating rami and thenmay a) bypass the sympathetic chain altogether, b) travel through thewhite ramus communicans, or c) travel through the gray ramus communicansthrough the chain to the white ramus communicans, on their way to thespinal cord through the dorsal root of the spinal nerve (cell bodieslocated in the dorsal root ganglion). Thus, these fibers are alsopresent within the paravertebral gutter coursing through or adjacent tothe sympathetic chain.

The peripheral branches from the upper thoracic trunk receive white ramifrom the upper thoracic sympathetic nerves. These vasomotor fibersinnervate the thoracic organs such as the lungs and aorta. Theperipheral branches from the lower thoracic trunk receive white ramifrom the lower thoracic nerves. These bundles are mainly distributed tostructures below the diaphragm and comprise the viscero-inhibitoryfibers for the stomach and intestines, motor fibers for part of therectum, pilomotor fibers for the lower part of the body, vasomotorfibers for the abdominal aorta and its branches, and for the lowerlimbs, secretory, and sensory fibers for the abdominal viscera(Cunningham 1913).

Another observation is the presence of intermediate or collateralsympathetic ganglia near the sympathetic chain. This has been observedat all levels of the sympathetic chain although these ganglia appear tobe more abundant in the lower thoracic and lumbar region. Theseaccessory ganglia can be found adjacent to the sympathetic chain, alongone of the rami communicantes, along the spinal nerve or a ramus of thespinal nerve, and even near the dorsal root ganglion. Intermediateganglia have also been found along the cardiac or pulmonary nerves asthe course to the organ, outside of the paravertebral gutter proper.These ganglia are thought to be a mechanism by which sympatheticefferent post-ganglionic fibers can be spared after sympathectomy inwhich surviving or adjacent pre-ganglionic nerves (with cell bodies inthe CNS) sprout to reinnervate these intact ganglia. In one embodiment,the ability of nerves to track to these ganglia is prevented by theplacement of a physical or other barrier in and around the paravertebralgutter to prevent sprouting neurons from reinnervating theseintermediate/accessory ganglia.

FIG. 1 illustrates neural anatomy at a single thoracic level. Eachspinal nerve separates into the dorsal (sensory) root 601 and theventral (motor) root 602 to enter the spinal cord 520. The dorsal root601 contains a spinal ganglia, the dorsal root ganglion 603, where thecell bodies of the sensory neurons are found. The roots lie in theintervertebral foramen and can be targeted indirectly by administrationof therapy to the paravertebral gutter which spreads to the region ofthe intervertebral foramen. Alternatively, therapy can be injecteddirectly into the intervertebral foramen to modulate the dorsal rootganglion 603, dorsal root 601, ventral root 602, or aberrant fibers thatare coursing to these structures.

The spinal nerve splits to form the dorsal 604 and ventral 606 primaryrami. The dorsal rami 604 supplies the back while the ventral primaryrami 606 supplies the lateral and anterior walls of the trunk via theintercostal nerve to the lateral and anterior cutaneous nerves. Asdiscussed above, the spinal nerves communicate with the sympathetictrunk with associated sympathetic ganglia 612 by way of the gray ramicommunicantes 608 and white rami communicantes 610 and thus carries bothsomatic and sympathetic fibers to the periphery. FIG. 1A is a close-upview of dotted circle 6A of FIG. 1 illustrating various structureswithin the paravertebral gutter 500 including the paravertebralsympathetic ganglia 612, gray ramus communicans 608, white ramuscommunicans 610, and visceral afferent and efferent fibers 614(innervating, for example, the heart and lungs). The cutaneous branchesof each spinal nerve (bilaterally) innervate one dermatome, or area ofskin surface. In the case of the first and second spinal thoracic nerve(T1 and T2 dermatomes), the medial (ulnar) surface of the arm andforearm. From a sympathetic perspective, this is relevant the vasculartone, skin temperature, sweating in these dermatomes. FIG. 1B is aclose-up view of dotted circle 6B of FIG. 1 illustrating the dorsal rootganglion 603 and ventral root 602.

Sympathetic innervation of the heart and lungs from the chain. Thecardiac and pulmonary sympathetic innervation derives mainly from theupper thoracic sympathetic chain (T2 to T6 or, in some cases T8), withthe majority of fibers originating in the first through fourth thoracicand traveling directly via post-ganglionic fibers to the heart and lungsor indirectly via preganglionic fibers that synapse on post-ganglionicnerves of the superior, middle, or inferior cervical ganglion. Thesepost-ganglionic fibers form the superior, middle, and inferior ‘cardiac’nerves that travel long the great blood vessels and form the superficialand deep thoracic aortic/cardiac plexus. Thus, pulmonary and cardiaccontributions from the cervical sympathetic ganglion (and the stellateganglion, in particular), are thought to be of thoracic origin althoughthere is some thought that there are unique contributions from thecervical ganglia. In addition, fibers from the upper six thoracicganglia (T1-T6) may travel back along the communicating rami to join theanterior roots of the thoracic spinal nerves and travel rostrally in thespinal column before existing to reach the third and fourth thoracicsegments (T3-T4). From here, the pre-ganglionic fibers continue in theupper thoracic intercostal nerves and the thoracic sympathetic trunk toterminate in one of the two or three cervical ganglion.

The fibers from the thoracic sympathetic chain, generally T1 to T4,cross the azygous vein on the right side and the aorta on the left sideto reach their cardiac and pulmonary targets. Some of the fibers passfrom the back of the root of the lung to the pulmonary plexus.

The superior cardiac nerve arises from the superior cervical ganglionand or occasionally from the trunk between the superior and middlecervical ganglia. The right superior cardiac nerve passes either infront or behind the subclavian artery, and along the innominate arteryto the back of the arch of the aorta where it joins the deep epicardialplexus. The right superior cardiac nerve also receives fibers from theexternal laryngeal nerve, vagus, and recurrent laryngeal nerve. The leftsuperior cardiac nerve runs in front of the left common carotid arteryand across the left side of the aortic arch to the superficialepicardial plexus.

The middle cardiac nerves arise from the middle cervical ganglia or fromthe trunk between the middle and inferior cervical ganglion. The rightmiddle cardiac nerve descends behind the common carotid artery and runsin front or behind the subclavian artery at the root of the neck andthen it descends on to the trachea, receiving a few filaments from therecurrent nerve and joins the right half of the deep epicardial plexus.This nerve also communicates with the right superior cardiac nerve andrecurrent nerve. The left middle cardiac nerve enters the chest betweenthe left carotid and the subclavian arteries and joins the deepepicardial plexus.

The inferior cardiac nerve arises from the inferior cervical ganglionand/or the first thoracic ganglion or stellate ganglion. Both right andleft inferior cardiac nerves travel behind the subclavian artery andalong the front of the trachea to join the deep epicardial plexus. Eachof these nerves communicates freely behind the subclavian artery withthe recurrent nerve and the respective middle cardiac nerve.

The post-ganglionic cervical fibers pass to the anterior pulmonaryplexus (lungs) via these cardiac sympathetic branches, including throughthe superficial and deep cardiac plexi. These fibers may travel alongthe pulmonary artery or across the pulmonary ligament and travelipsilateral and contralaterally.

The deep cardiac (or epicardial) plexus lies in front of the trachealbifurcation and behind the aorta/aortic arch and rostral to the divisionof the pulmonary artery. This plexus contains cardiac sympathetic fibersfrom all of the right and left cervical sympathetic ganglia (with theexception of the left superior cervical ganglion/left superior cardiacnerve). The plexus also receives innervation from the superior andinferior cervical and thoracic branches of the right vagus nerve andsuperior cervical and thoracic branches of the left vagus nerve. Theseneurons may be pre- or post-ganglionic. The plexus goes on to form aleft coronary (ventricle), right coronary (ventricle), ventral rightatrial, ventral left atrial, left dorsal (atrium/ventricle), middledorsal (left: atrium/ventricle), and dorsal right atrial subplexuses.Anatomists suggest that left subplexuses are typically from the leftside of the deep cardiac plexus and the ventral and dorsal subplexusesare from the right preganglionic sympathetic and vagus as their branchescourse in the adventitia of the right pulmonary artery and superior venacava.

The superficial cardiac (or epicardial) plexus lies in the concavity ofthe aortic arch and in front of the right pulmonary artery. Thesuperficial plexus receives contributions from the left superiorcervical ganglion and the lower superior cervical cardiac branch of theleft vagus. The superficial plexus is closely connected with the deepcardiac plexus as well as the anterior and posterior pulmonary plexus.Fibers from the cardiac plexus also pass on to the pulmonary plexus andvice versa. The branches from the right half of the deep cardiac plexuspass in front or behind the pulmonary artery. Those that pass in frontof the pulmonary artery send fibers to the anterior pulmonary plexus andthen continue on to the anterior coronary plexus (right atrium andventricle). The deep fibers that pass behind the pulmonary plexusdistribute fibers to the right atrium and then on to the posteriorcoronary plexus. The branches from the left half of the deep cardiacplexus are connected with the superficial cardiac plexus and givefilaments to the left atrium and to the anterior pulmonary plexus andthen on to form the greater part of the posterior coronary plexus (leftatrium and ventricle). Thus the cardiac and pulmonary plexuses are incontinuity with one another.

Sympathovagal interconnectivity. The sympathetic fibers frequentlyanastomose with the vagal fibers. Cervical sympathetic fibers are alsothought to be distributed to the vagi on both the ipsi- andcontralateral sides. Sensory afferent fibers from the lung, whoseganglia are found primarily in the nodose ganglion run principally inthe vagi but also to some extent in the sympathetic trunks. Similarly,some clinicians believe that bronchoconstrictor fibers from the rightand left vagus are given off high in the neck and course down theipsilateral or contralateral sympathetic trunk. From there they leavethe trunk and join the posterior pulmonary plexus.

Sympatho-somatic interconnectivity. There are variable intrathoracicconnections between the first, second, third, and fourth intercostalnerves and the brachial plexus which result in abnormal connectionsbetween the sympathetic chain and the brachial plexus. These connectionsare thought to contribute to failed sympathectomy.

Parasympathetic Innervation to and in the Lungs.

Vagal fibers run from the dorsal vagus nucleus in the vagal nerve trunkwithout interruption until they reach the lung hilum. The vagus extendsbranches to the lung from at or just above the level of the recurrentnerve to and along the pulmonary ligament. From the hilum, the vagalfibers divide into numerous small branches which mainly innervate theipsilateral but also the contralateral lung. These branches form a partof the posterior pulmonary plexus on the right and left side and end inthe ganglions situated along the posterior surface of the main orprimary bronchi. From these ganglions the postganglionic fibers aredistributed throughout the lung to the bronchial musculature.

Vagal fibers course along the pulmonary artery, superior pulmonary veinand pulmonary ligament. Vagal innervation is more extensive on the leftside of the lung than the right. On the left side there are tworelatively large fibers bundles which travel in and about the sheath ofthe pulmonary artery and two large branches to the left bronchus. Inaddition, on the left, four to eight major filaments are distributedbetween the pulmonary artery and bronchus. On the right side there areusually only two or three main branches and two to four finer filaments.Compared to the left side, a greater portion of the nerve trunks go tothe main bronchus on the right side with relatively less going to thepulmonary artery. The nerve supply to the artery is less than that tothe bronchus but is abundant. No large parasympathetic branches are seengoing to the sheath of the veins.

Vagal fibers to the heart. The lung is innervated by efferent andafferent autonomic nerves supplied by the sympathetic andparasympathetic nervous system. Together, their fibers anastomoseextensively with one another on the posterior surface of the hilum toform the posterior pulmonary plexus as well as on a smaller anteriorpulmonary plexus. Vagal and sympathetic contributions are from bothipsilateral and contralateral origin. Both the sympathetic andparasympathetic are connected by a reflex arc via the respiratory centerin the medulla.

These nerves regulate many aspects of airway function including airwaysmooth muscle tone, airway secretion, bronchial circulation,microvascular permeability, and the recruitment and activation ofinflammatory cells. The innervation to the lung originates primarilyfrom the larger posterior pulmonary plexus and secondarily the smalleranterior pulmonary plexus. These plexi are formed by both fibers fromthe sympathetic and vagal (parasympathetic) arms of the autonomicnervous system. There are as many sympathetic fibers entering theposterior pulmonary plexus as vagal fibers. The main bundles of thevagus are joined by numerous minute filaments deriving from thesympathetic chain and from other intrathoracic plexuses. These fibersare then redistributed in a succession of bronchial and submucousplexuses. Overall, myocardial tone, vascular tone, and/or airway smoothmuscle tone are thought to be dependent on several factors, includingparasympathetic, sympathetic, circulating factors such as epinephrine,NANC inhibitory and excitatory nerves as well as sympathetic innervationof the parasympathetic ganglia.

Airways. The parasympathetic nerves are the dominant neural pathway inthe control of airway smooth muscle tone and airway secretion. The majorneurotransmitter of cholinergic nerves is acetylcholine (ACH) whichbinds to muscarinic receptors. Stimulation of cholinergic nerves causesrelease of ACH resulting in bronchoconstriction, mucus secretion, andbronchial vasodilation. Cholinergic nerves also contain vasoactiveintestinal peptide (VIP) and nitric oxide (NO) which are thought to actas co-transmitters with and functional antagonists to ACH. VIP receptorson these nerves (and NO through an unknown mechanism of action) bind toVIP and cause smooth muscle relaxation (see below).

Inhibitory nonadrenergic noncholinergic (iNANC) nerves may be the onlyneural bronchodilator pathway in human airways. These nerves releasevasoactive intestinal peptide (VIP), nitric oxide (NO), peptidehistidine methionine (PHM), and pituitary adenylate cyclase-activatingpeptide (PHM) and are frequently distributed close to parasympatheticnerves. Some of these neurotransmitters have also been co-localized withACH in parasympathetic nerves. Research supports their role as afunctional antagonist to cholinergic bronchoconstriction and proposethat they act prejunctionally to inhibit ACH release. VIP receptors arealso localized in pulmonary vascular smooth muscle, airway smooth muscleof large airways, airway epithelium, and submucosal glands. VIP is oneof the most potent relaxants of smooth muscle and has also beendemonstrated to stimulate mucus secretion, vasodilate pulmonary vessels,inhibit mediator release from mast cells, inhibit T lymphocyteproliferation, interleukin release from bronchial epithelial cells, andregulate isotype switching in B lymphocytes. Nitric oxide synthase(NOS)-containing nerves are found in tracheal and bronchial smoothmuscle, around submucosal glands and around blood vessels where NOproduction may result in hyperemia, plasma exudation, mucus secretion,and skewing T lymphocytes towards a Th2 phenotype. Excitatorynonadrenergic noncholinergic (eNANC) nerves have also been identified inhuman airways and stimulation of these nerves in animals has beenresults in bronchoconstriction, mucous secretion, vascularhyperpermeability, cough, and vasodilation. This process is collectivelycalled ‘neurogenic inflammation’ and has been demonstrated to be aresult of the interaction between eNANC nerves and inflammatory cells.These neurons are a subpopulation of nonmyelinated sensory C fibers thatrelease neuropeptide Y (NPY) and are the classic nociceptive neuronsthat transmit sensations of itch and pain associated with tissue injury.These neurons are stimulated by exogenous substances such as cigarettesmoke, capsaicin or inhaled irritants and by endogenous substances likehistamine, bradykinin and prostaglandin. Interestingly, these neuronsalso release neuropeptides in a ‘neuroeffector’ mechanism so theireffects exert a local axon reflex. eNANC neurons release calcitoningene-related peptide (CGRP), secretoneurin, the tachykinins (TK):substance P (SP) and neurokinin A (NKA) in addition to NPY. CGRP and NPYhave potent vasodilatory effects and may also modulate immune cellfunction. CGRP, in particular, mediates long-lasting vasodilationthrough its direct action on receptors on vascular smooth muscle (lesseffect on smooth muscle or epithelial cells in human airways). CGRP hasno effect on microvascular leak but may amplify SP-induced proteinplasma extravasation and it may indirectly mediate bronchoconstriction.The TKs exert a wide variety of effects on smooth muscle cells,submucosal glands, epithelial cells, blood vessels, nerves, and immunesystem cells. NPY is thought to have no direct effect on airway smoothmuscle but may cause bronchoconstriction indirectly via release ofprostaglandins. SP induces venular vasodilation, increased vascularpermeability, and immunoreactive nerves can be found in airwayepithelium, around mucosal arterioles and submucosal glands, withinbronchial smooth muscle and around local parasympathetic ganglia. SP andNKA receptors, NK1 and NK2, are primarily responsible for mediating theinflammatory effects of the TKs. The NK1 receptors are found on smoothmuscle, pulmonary vessels, airway epithelium and submucosal glands wherethey mediate mucus secretion in peripheral airways and microvascularleak in postcapillary venules. They also play a role in clearing mucus,bacteria and inhaled particles by increasing ciliary beat frequency,releasing prostaglandins, and are involved in the migration andproliferations of bronchial epithelial cells. SP may be involved in therecruitment of neutrophils to airways and the activation andproliferation of fibroblasts. The NK2 receptors have not been fullycharacterized but have been demonstrated to mediate bronchoconstriction.Here, NKA is considerably more potent than SP and the effect issignificantly greater in smaller bronchi than more proximal airways,suggesting that these peptides have a more important constrictor effecton more peripheral airways. Some evidence suggests that TKs may amplifycholinergic neurotransmission and modulate iNANC-mediatedbronchodilation, contributing to exaggerated (van der Velden andHulsmann 1999). TKs appear to mediate neutrophils (chemotaxis,aggregation, superoxide production, adherence), eosinophils(recruitment, degranulation), T lymphocytes (proliferation and cytokineproduction, chemotaxis), mast cells (histamine release),monocytes/macrophages (release of inflammatory cytokines), B lymphocytes(differentiation, immunoglobulin isotype switch), and dendritic cells(chemotaxis, antigen presentation).

Sympathetic efferent nerves are less abundant and are thought to playless of a role in the human airways relative to the parasympatheticnerves. They are primarily present in close association with submucosalglands and bronchial arteries although some researchers believe theyhave found non-myelinated efferent fibers within bronchiolar smoothmuscle and alveolar ducts. The primary pre-ganglionic sympathetic(extrapulmonary) neurotransmitter is acetylcholine although nitricoxide, CGRP, VIP, substance P and encephalin have also been localized topre-ganglionic nerve endings. Post-ganglionic sympatheticneurotransmitters are differentially released into the peripheral targettissue as a function of how they are stimulated. The main sympatheticneurotransmitters of sympathetic efferent post-ganglionic nerves arenorepinephrine (noradrenaline) and the co-transmitter NPY which activateα- and β-adrenergic receptors. Other neurotransmitters andco-transmitters include ATP, NPY and enkephalins. Sympatheticinnervation of human airway smooth muscle has not been observed althoughβ2 adrenergic receptors are abundantly expressed on these cells and arepresumed to be regulated in part by circulatingepinephrine/norepinephrine released from non-pulmonary stores. However,adrenergic nerves may influence bronchomotor tone indirectly viaprejunctional α- and β-adrenergic receptors. β-2 adrenergic receptorsare abundantly expressed on human airway smooth muscle and epithelialand mast cells and activation of these receptors causesbronchodilation/bronchorelaxation. β1 receptors are found in humansubmucosal glands and alveolar walls. The α1 adrenergic receptor,mediating the contraction of smooth muscle, is relatively sparse.Prejunctional α2-adrenergic receptors may inhibit the release ofnorepinephrine and NPY from adrenergic nerves. Similarly, α2-adrenergicreceptors may inhibit the release of tachykinin from sensory nerves.Cholinergic neurotransmission may also be inhibited via α2-adrenergicreceptors.

Vascular Innervation of the Lung.

From posterior pulmonary plexi, the pulmonary arteries receive a plexusof large parasympathetic and sympathetic nerve trunks coursing throughthe adventitial and periadventitial layer. Most of the fibers are foundin the larger elastic arteries, fewer in the muscular arteries, andfibers are absent in vessels smaller than 30 μm. There is especiallydense innervation of a population of arterioles arising at right anglesfrom the pulmonary arteries which may play a role in the distribution ofblood flow in the lungs. The majority of these fibers are myelinated butthere are also smaller nonmyelinated fibers. Terminal twigs pass to theouter-third of the media where they travel to the smooth muscle cells ofthe media in the large elastic arteries. In the smallest musculararterioles, these fibers remain external to the medial coat. Musculararteries are supplied exclusively by fine fibers and there arerelatively fewer fibers in the pulmonary veins. Axons with vesicle-richsegments are usually separated from muscle cells by the external elasticlamina and fibrocyte processes. Muscle cells, will extend pinocyte-richvesicles across the EEL to these axons providing a nerve-muscle gap of100 nm, and consistent with neurotransmission via transmitter diffusionfrom specialized regions of the axon.

Sympathetic nerves may be the primary neuronal pathway controlling thetracheobronchial blood vessels. Stimulating the sympathetic nerve fibersresults in vasoconstriction of segments of the larger pulmonary vessels,but not those less than 0.6 mm in some cases. In some embodiments,sympathetic neuromodulation is effected herein without or withoutsubstantially ablating, denervating, or otherwise neuromodulatingparasympathetic nerve fibers.

Cervical Ganglia. Innervation of portions of the face including themeninges, pupils, salivary glands, arteries, and sweat glands, arisefrom post-ganglionic cervical ganglion (including stellate ganglion)neurons ascending along the internal carotid body. Innervation of theposterior scalp and neck also originates post-ganglionic motor neuronsfrom the superior cervical ganglion. Innervation of the brachial plexusoriginates from the middle and inferior cervical nerves and the chestand abdominal wall from the thoracic nerves.

Lower Thoracic, Lumbar, and Splanchnic Ganglia. Innervation of lowerextremities originates from spinal cord segments T10 to L3 and areconveyed primarily through L1 to L4 ganglia. L1 and L2 ganglia arefrequency fused and L2 and L3 ganglionectomy is usually sufficient toameliorate symptoms of a variety of lower extremity conditions.

Indications for modulation of cervicothoracic sympathetic tone includediseases with persistent, adverse activation of sympathetic outflow tothe heart and lungs including ongoing episodic sympathetic activation ofcardiopulmonary, cardiac, pulmonary, arterial or venous target tissues,and defective neural reflexes, including sympathetic circulatoryreflexes. While sympathetic overactivity of the kidneys and peripheralcirculation mediates systemic adverse effects through vasoconstrictionand increasing the work of the heart and by promoting sodium retentionand ventricular overfilling, it is the sympathetic overactivity of theheart itself that is potentially the most damaging. For a time, thisstimulation provides support to the failing myocardium but it leads tothe development of ventricular arrhythmias, progressive left ventriculardeterioration and mortality in a vicious positive feedback loop.Reduction of sympathetic tone in the thoracic cavity has a beta-blockinglike effect, and to some extent, an alpha-blocking like effect, causinga reduction in heart rate, reducing myocardial oxygen demand, increasingdiastolic perfusion time resulting in increased myocardial perfusion.Through an alpha-blocking like effect, reduction in sympathetic tone mayhave a vasodilatory effect or at least a protective effect againstvasoconstriction. These combine to reduce angina symptoms and ischemia.Reducing afferent activity results in a reduction of activation ofnociceptors which some researchers suggest have been sensitized, orconverted from high-threshold to low-threshold nociceptors.

In some embodiments, treatment results in at least an amelioration ofthe symptoms associated with the pathological condition afflicting thepatient, where amelioration is used in a broad sense to refer to atleast a reduction in the magnitude of a parameter, e.g. symptom,associated with the pathological condition being treated. As such,treatment includes situations where the pathological condition, or atleast symptoms associated therewith, are completely inhibited, e.g.prevented from happening, or stopped, e.g. terminated, such that thepatient no longer suffers from the pathological condition, or at leastthe symptoms that characterize the pathological condition.

In some embodiments, systems and methods as disclosed herein aredirected to modulating the sympathetic nervous system to the thoraxtargeting the cervical and upper thoracic sympathetic fibers, such, asfor example, from the T1 to T5 paravertebral gutter, including one, two,or more of the following: T1, T2, T3, T4, and T5. Since the T1 gangliais frequently fused with the cervical ganglia, the inferior cervicalganglion, procedures that block or ablate these ganglia are generallyreferred to as cervicothoracic sympathetic block or cervicothoracicsympathectomy, respectively. In some embodiments, treatingcardiothoracic conditions through the delivery of neuromodulatory agentsto the cervical ganglia may be desirable, however these are more likelyto have off-target effects whether as a result of the procedure itself,the therapy spreading to non-target tissues and nerves, or undesirableside effects to the head and neck as result of modulating the cervicalganglia. In some embodiments, the treatment of cardiopulmonaryconditions is achieved through the delivery of neuromodulatory agents tothe thoracic sympathetic ganglia as well as the variable number of ramicontaining both afferent and efferent fibers that emanate from thechain, the roots, and the intercostal nerve. More specifically, thesympathetic chain together with the visceral rami or fibers travelingfrom the sympathetic chain directly or indirectly to the viscera aretargeted. This can be achieved through the delivery of neuromodulatoryagents into the paravertebral gutter.

Pulmonary.

In some embodiments, disclosed herein are systems and methods fordecreasing the activity of the sympathetic arm of the autonomic nervoussystem to treat pulmonary diseases, including but not limited to asthma.The therapy may prevent, reduce the symptoms of, ameliorate, or cureasthma and comorbid diseases. The therapy may also be directed towardthe prevention or treatment of other pulmonary diseases including butnot limited to emphysema, pulmonary artery hypertension, chronicobstructive pulmonary disease, acute respiratory distress syndrome,pulmonary edema, pneumonia, pulmonary thromboembolism, chronic cough,acute or chronic bronchitis, cystic fibrosis, bronchiectasis,bronchopulmonary dysplasia, pulmonary fibrosis, interstitial lungdisease, pulmonary edema, pleurisy, bronchiolitis, bronchialhyperresponsivity (BHR), acute respiratory distress syndrome (ARDS),and/or pain associated with lung and other tumors.

Asthma.

Disruption or denervation of the upper thoracic sympathetic chain canresult in denervation of the sensory afferent and efferent fibersinnervating the lungs, pulmonary arteries, bronchial arteries, andpleura. Based on preclinical and clinical research, sympatheticdenervation may be helpful in 1) increasing pulmonary vascular dilation,reducing pulmonary vascular tone and thus reducing pulmonary pressures,improving oxygen transport and clearance of irritants from the lung; 2)reducing the local inflammatory response that occurs during an asthmaattack, reducing eosinophil and neutrophil activation; 3) improvedlymphatic clearance and a reduction in lung edema; 4) reduce mucushypersecretion; 5) reduce local norepinephrine spillover in the lungsand the heart; and 6) possibly result in bronchodilation.

Pulmonary Artery Hypertension.

Given the beneficial effects observed preclinically and clinically inthe treatment of pulmonary artery hypertension with local sympathetic(afferent, efferent) denervation of the nerve bundles coursing over andthrough the pulmonary arteries, pulmonary artery trunk and the nearbypulmonary and cardiac plexi, a more complete sympathetic denervation tothe pulmonary arteries (and cardiopulmonary tissue generally) may bedesired by delivering the therapy to the T1-T4/T5, or T2-T4paravertebral gutter in some embodiments. This may be particularlydesirable given the long distances that some of the extra-pulmonaryartery nerves and plexi are from the vessel and thus the long distancesthat a chemo- or thermo-ablative therapy can travel to denervate thesenerves. This also may be preferable in some cases over pulmonary arteryregional denervation since these fibers are mixed sympathetic andparasympathetic nerves.

Alternatively, given the controlled nature afforded by the deposition ofthe therapy, the ability to fill a potential space and subsequentcontrol the spread of the neuromodulatory agent, comprising, forexample, a neuromodulatory agent in a hydrogel, it may be desirable todeliver the therapy directly outside the pulmonary artery and veins forthe treatment of pulmonary artery hypertension, as opposed to theuncontrolled spread of a conventional neurolytic agent such as ethanol.The therapy may result in improvements in endpoints such as change(e.g., decrease) in BNP, change in 6 minute walk test (6 mwt), change inDoppler derived mean pulmonary artery pressure, blood pressure,pulmonary capillary wedge pressure, cardiac output, quality of life andmortality, and/or other parameters. These patients may also benefit froma dramatic reduction in the number of costly medications they areprescribed. This local approach has applications beyond the treatment ofpulmonary artery hypertension since the pulmonary arteries and pulmonarytrunk sit adjacent to the lower curvature of the aortic arch, where thecardiac (and pulmonary) plexi sit, largely adherent to the aorta. Thusdelivery of a therapy here may have broader benefits in the treatment ofcardiopulmonary conditions.

Angina and Refractory Angina.

Angina pain reduction by cervicothoracic sympathetic block or ablationis thought to be a result of the disruption of the pain signal relayedin the afferent visceral nerve fibers as well as reduced work of theheart through sympathetic efferent nerve disruption resulting indecreased norepinephrine release and binding to beta-adrenoreceptors.This beta-blocker-like effect can result in a reduction in cardiaccontractility, reducing myocardial oxygen demand thereby reducingischemia and thus ischemic-pain. A secondary vasodilatory effectfollowing coronary blockade of alpha-adrenoreceptor mediated sympatheticvasoconstriction. The majority of these afferent and efferent fibers arerelayed through the left stellate and left thoracic ganglia althoughthere are bilateral projects to the left ventricle. Prolonged painrelief (weeks) after the administration of a short-acting localanesthetic to the stellate ganglion may potentially be explained througha down-regulation or resetting of the hypersensitive nociceptivepathway. The volume of anesthetic administered spreads unpredictably andin some portion of patients it travels down the paravertebral gutter toblock variably to T2 or, in some cases, spreads down to T6, and mayaccount for the variability in efficacy of the anesthetic blocks. Thestellate anesthetic blocks need to be repeated every 2 to 6 weeks as theangina pain returns, at additional cost and increased safety risks fromrepeated procedures. If these blocks are repeated for over 6 to 9months, anecdotal clinical evidence suggests that these blocks maybecome more long-lasting and in some cases permanent, perhaps due to thecumulative local toxicity of the anesthetic and/or chronic localinflammatory response from these injections. A more long-lasting and/orpermanent therapy that is easily administered, specifically targetable,and more importantly, has an excellent safety profile, can be desirablein some embodiments, particularly one that involves a one-timeoutpatient procedure to treat the condition. The procedure could beperformed with intravenous sedation and local anesthesia or with a localanesthetic alone.

Both stellate ganglion blocks and open surgical stellate orcervicothoracic sympathectomy has been demonstrated to relieve severeangina pectoris, and in many cases alleviating all angina pain. Anginapatients typically have coronary artery disease (CAD), particularly aspatients are living longer with the advent of coronary revascularizationtechnologies. Stated another way, the therapy has the potential to treatpatients with coronary artery disease, whether it be present in thecoronary arteries sufficient to cause a >50% occlusion of these vessels,be present but be less than 50% occluded, or be absent in the coronaryarteries and present in the smaller distal arterioles and capillariesfeeding the heart. Thus, angina is one of the symptoms of coronaryartery disease. In one embodiment, patients with chronic refractoryangina (greater than 3 months of angina, reversible ischemia) thetherapy is delivered to the T1 to T5 paravertebral gutter, such as theT2 to T4 paravertebral gutter to treat angina and patients' weeklyangina attack frequency decreases, nitroglycerin consumption is reducedand maximum exercise capacity increased, and/or decrease in heart rateand blood pressure and reduction in ST-segment depression. The proceduremay be performed, for example, endovascularly or transcutaneously. Inanother embodiment, patients that have undergone percutaneous coronaryintervention (PCI) or coronary artery bypass grafting (CABG) but haveachieved incomplete revascularization and/or have persistent or ongoingangina are treated in some aspects. In another embodiment, patients thathave persistent or ongoing angina due to coronary artery disease but areunsuitable for PCI/CABG because of instability or procedural risk,number of vessels, procedural access etc. may be treated in someaspects. In yet another embodiment, the procedure can be performed as anadjunctive procedure to percutaneous coronary intervention (PCI) orcoronary artery bypass (CABG) to relieve angina through, for example,the endovascular route with PCI and the transcutaneous or under directvisualization with CABG. Although this procedure can be performed forthe treatment of angina, it can also be performed to reduce the risk ofatrial and ventricular arrhythmias, reduce pre- and post-proceduralvasospasm and potentially reduce the primary and secondary ischemic zonearound an infarct. In some cases, the therapy is delivered to thepatient prior to the start of surgery in order to have maximal clinicaltherapeutic benefit. In another embodiment, with the establishment ofthe safety of the procedure, the therapy can be delivered on anoutpatient basis or elective basis to high-risk cardiac patients fortemporary or permanent sympathectomy to treat both the underlyingdisease and/or their symptoms. In another embodiment, the therapy can bedelivered to the approximately 30% of cardiovascular patients thatcannot, for one reason or another, tolerate or be compliant to thetherapeutic dose of their beta-blocker therapy.

Microvascular Disease. Of the patients with angina but no angiographicevidence of CAD, 50-65% of patients have coronary microvasculardysfunction (CMD) also known as microvascular coronary dysfunction(MCD). These patients are considered a higher risk subgroup of patientswithin Cardiac Syndrome X (CSX). Within women, 50-60% with angina haveno obstructive CAD (>50% luminal diameter stenosis in ≧1 epicardialcoronary artery), twice as often as men. These women have increasedphysician visits, increased hospital admission rates for angina, repeatinvasive examinations and loss of quality of life and ability to work.MCD patients, frequently younger women, present with persistentworsening exertional chest pain, abnormal stress testing, the absence ofobstructive coronary artery disease through coronary angiography andnormal left ventricular function. In these patients, coronary reactivitytesting (CRT) demonstrates a limited coronary flow reserve (CFR) toadenosine infusion and coronary blood flow reserve and coronary arteryconstruction with acetylcholine, indicative of endothelial dysfunction.Adenosine stress cardiac magnetic resonance imaging demonstrates reducedperfusion during stress. Management of these patients can be challengingbecause they have ischemic-type ST-segment depression and noninvasivestress testing reveals perfusion/wall-motion abnormalities. Thesepatients were thought to have a benign prognosis however data from theNHLBI-WISE study shows that up to 50% of these patients have MCD whichis associated with a 2.5% annual adverse cardiac event rate includingmyocardial infarction, stroke, hospitalization for congestive heartfailure, and sudden cardiac death. In this disease, the small arteriesand arterioles downstream of the epicardial coronary arteries are themajor sites of resistance to blood flow. Given that beta-blocker therapyis the first-line drug therapy for this indication and that sympatheticefferents also modulate coronary vascular and microvascular tone, thesepatients could benefit from a procedure to reduce sympathetic componentof their disease, thereby treating both the symptoms (pain) and theunderlying disease. In one embodiment, the aforementioned tests are usedto stratify patients that are suitable for the procedure (Marinescu etal 2015). In particular, tyramine testing or adenosine testing forresponsiveness are examples of tests that can be utilized. In oneembodiment, the 10-30% of patients undergoing diagnostic angiography fordiagnosis of CAD but have no evidence of the coronary artery diseasedespite ongoing ischemia-symptoms, such as angina, are treated with thetherapy targeted to the T1-T4 paravertebral gutter unilaterally, suchas, for example, on a first side of the paravertebral gutter, such asthe left side. If symptoms are incomplete, a second side, such as theright side of the paravertebral gutter can be treated.

Atrial or ventricular arrhythmias. Development of cardiac sympatheticheterogeneity after myocardial infarction contributes to the lowering ofthreshold for ventricular arrhythmias and sudden cardiac death,particularly in the first 30 days after MI. This is hypothesized becauseof the close proximity of two zones of tissue: 1) sympatheticallydenervated tissue in the peri-infarct zone, in which thebeta-adrenoreceptors on the myocardiocytes and other cells have becomehypersensitized and 2) sympathetically hyperinnervated tissue, in whichlocal ischemia and neuronal damage have triggered sympathetic nervesprouting. Because these zones are close to one another, norepinephrinereleased from a hyperinnervated zone may exert its effects on the highdensity of beta-adrenoreceptors on the myocardial tissue, causing achange in the threshold for arrhythmias, and triggering an arrhythmia.In some embodiments, the arrhythmia to be treated can be, for example,atrial fibrillation, atrial flutter, paroxysmal supraventriculartachycardia, monomorphic or polymorphic ventricular tachycardia (VT), orventricular fibrillation (VF). Patients may have sustained VT ornonsustained VT.

Ventricular arrhythmias. Patients may develop arrhythmias as a result ofnon-ischemic cardiomyopathy (NICM), ischemic cardiomyopathy, myocardialinfarction, HCM, Sarcoid cardiomyopathy, ARVD, HOCM, and the like.

Some patients with implantable ICDs have recurrent ventriculartachycardia (VT). These patients may also undergo a catheter-basedand/or epicardial VT ablation procedure and continue to suffer recurrentVT. These patients may in some cases be particularly suitable for thetherapy described.

A reduction in ICD shocks, or the debilitating fear that some patientshave that they might have an ICD shock, can be meaningful to thesepatients. As a result of the concern of having an ICD shock, manypatients significantly limit their physical activities, causing adecline in their quality of life. These patients may become depressed.Providing these patients with an alternative to an ICD would bebeneficial to these patients. Alternatively, providing patients and/orclinicians with a procedure that may improve the efficacy of the indexprocedure with limited additional safety risks, would be attractive.

Therefore the therapy can be beneficial treating patients: 1)prophylactically, at high risk for VT and SCD who have not yet had arecorded or observed event, 2) who, as a result of monitoring (Holtermonitor, implanted (REVEAL LINQ), or as part of their pacemaker or otherimplant), have been diagnosed with VT, 3) with VT or other conditions inwhich an ICD would be recommended but the patient refuses or thehealthcare system/patient cannot afford the cost of an ICD, 4) with anICD but would like to reduce their concern that they will have an eventresulting in ICD firing, even if it is appropriate, 5) with an ICD butsuffer from inappropriate device firing, particularly since it is sopainful 6) who have an ICD explanted and require some protection fromsudden cardiac death, 7) that are high risk for an MI and would like tohave the therapy performed prophylactically to reduce their chances ofsudden cardiac death, 8) who have had an MI (acutely) and are at highrisk for arrhythmias in the next 30-60 days, 9) who are undergoing PCIor CABG and would like some prevention from the post-operativearrhythmias, 10) refractory patients who have undergone VT ablation orwho have VT or VF that is not ablatable and 11) patients undergoinghemodialysis who have a high rate of fatal arrhythmias and 12) patientswith a CRT-D that are at high risk for arrhythmias and 13) withventricular storm, particularly refractory or incessant ventricularstorm, 14) with an ICD after surviving SCD, 15) suffering from syncopedespite maximal beta-blockade and 16) that have had prior AF ablation,SVT ablation, VT ablation (SHD or idiopathic) that would otherwise beundergoing a first or second VT ablation procedure. In settings in whicha precipitating cardiac event requires treatment, these procedures canbe performed as a standalone or adjunctive procedure (adjunct to VTablation, CABG, PCI, ICD implantation, AF ablation) and if the therapyis demonstrated to be safe, it can be used for secondary and primaryprevention of arrhythmias. Alternatively, the therapy can be deliveredon an elective basis during the course of ongoing drug treatment of apatients cardiac arrhythmias and other comorbidities, such as after orin conjunction with a diagnostic EP study. The procedures may be firstperformed as an anesthetic block to the target levels, for example, astellate or cervicothoracic or thoracic paravertebral block, and then,pending the efficacy of the block or the challenges with repeatedblocks, the block can be converted to a permanent solution, eitherduring the same or a secondary procedure, to the delivery of aneurolytic in a hydrogel.

In some embodiments, a sympathetic neuromodulation procedure asdescribed herein is performed in conjunction with ablation of anarrhythmic focus which may be performed with an endovascular orepicardial approach. Recently, clinical several trials have beeninitiated to study the effects of bilateral cervicothoracicsympathectomy for the prevention of ventricular tachyarrhythmias(PREVENT-VT, NCT01013714) or other sympathetic denervation approaches(RESET-VT, NCT01858194). Specifically, therapy delivered from T1 to T4may have beneficial effects in freedom from ICD shocks, time to firstevent requiring ICD therapy or refractory/incessant VT, number of ICDshocks, occurrence of VT storm, occurrence of ICD storm, total VTburden, and survival free of ICD shock. Clinical data to date suggeststhat between 50-65% of patients have a complete clinical responsefollowing bilateral VT. Preclinical and clinical studies haddemonstrated a reduction in VA occurrence, improved ventricularelectrical stability, mean arterial pressure and infarct size (in acuteMI applications). Treatment of VT or VF includes the delivery of thetherapy to the stellate ganglion alone, T1 alone, or T1 to T4.

Atrial fibrillation. The autonomic nervous system can induce atrialtachyarrhythmias including atrial tachycardia and atrial fibrillation.Paroxysmal and persistent atrial fibrillation may be treated with acombination of the PVI isolation (or another existing catheter-basedprocedures that target and ablate the aberrant cardiomyocyte circuits)in combination with left and or right/sided paravertebralneuromodulation at the T1 to T4 levels. Alternatively, theneuromodulation gel may be delivered both into the paravertebral gutterand to the epicardial fat pads containing the ganglionated plexi(sympathetic, parasympathetic, interneurons).

Atrial fibrillation is one of the most widespread problems encounteredafter cardiac surgery, prolonging morbidity, mortality and duration ofhospitalization. Atrial fibrillation and C-reactive protein levels havebeen demonstrated to peak at 2 days post-cardiac or non-cardiac surgeryand then subside within a week. Furthermore, atrial fibrillation isassociated with higher rates of stroke, CHF, and late AF in patientsundergoing coronary artery bypass graft (CABG), aortic valve or mitralvalve surgery. Postoperative AF (POAF) is maximal within two or threedays after and remains high for a week after the procedure. In oneembodiment, the sympathetic nervous system is partially or completelydenervated in the region of the paravertebral gutter to block one of thetriggers for the induction of atrial fibrillation.

Chronic heart failure. Disruption or denervation of the uppersympathetic afferent and efferent fibers results in denervation of theaortic arch baroreceptors and possibly the carotid baroreceptors andchemoreceptors, manifesting for example as a reduction in heart rate,heart rate variability and modulate ventilatory drive. Not to be limitedby theory, sympathectomy may have a partial beta-blocker like effect,not only reducing the threshold for arrhythmias but triggering reverseremodeling in the heart. As a result, these changes may result in apositive improvement in chronic heart failure and a reduction in bloodpressure. In a limited clinical study in which left lower ⅓^(rd) of thestellate ganglion and T3-T4 videothorascopic clipping, patients withsystolic heart failure had improved left ventricular ejection fraction(LVEF). Patients with heart failure can be further broken down intotheir risk category based on their LVEF with patients with lower LVEF(<35%) being at highest risk for cardiac arrhythmias more than patientsbetween 35-45% LVEF (intermediate risk) and patients >50% LVEFconsidered to have low risk of arrhythmias.

Myocardial infarction. Sympathetic nerves play a significant role in theinitiation of acute myocardial ischemia as well as being subsequentlyfurther activated by ischemia, further aggravating the condition.Cardiac sympathetic denervation may in some cases result in reducedalpha-1 and alpha-2 adrenoreceptor mediated coronary vasoconstriction,the reduced alpha-1 mediated (epicardial) coronary artery spasm.

Other cardiac indications. Cardiac indications are typically treated bymodulating the left sympathetic chain and then, as necessary to maximizeefficacy, the right sympathetic chain although bilateral procedures areincreasingly performed. Other cardiac indications for long-duration orpermanent therapy directed towards the T1 to T4/5 paravertebral gutterand other anatomical targets include both ischemic and non-ischemiccardiac pain including Cardiac Syndrome X, Cardiac Syndrome Y (slowcoronary flow), coronary artery spasm or Prinzmetal angina, aorticstenosis, left ventricular hypertrophy, mitral valve prolapse and othervalvular diseases, abnormal cardiac nociception, and no reflow patients.In addition the therapy can be delivered to treat hypertension,including essential hypertension, secondary hypertension, andparticularly neurogenic, obesity-related hypertension, benignhypertension, malignant hypertension, hypercatecholaminergichypertension, as well as disorders of postural circulatory controlcausing syncope, acute or chronic heart failure, ischemic andnon-ischemic cardiomyopathy, dilated cardiomyopathy, arrhythmogenicright ventricular cardiomyopathy, myocardial contractility disorder,acute coronary syndrome, compensated or decompensated or uncompensatedheart failure, congestive heart failure, acute heart failure,early-stage heart failure, severe congestive heart failure withpreserved ejection fraction (HFPEF), stress (takotsubo) cardiomyopathy,acute mental stress leading to angina, panic attacks accompanied bycoronary artery spasm, mitral valve disease, aortic valve disease,psychogenic cardiovascular disease (heart disease attributable to stressor mental illness), ischemia and infarct size associated with myocardialinfarction, patency or lack thereof of radial artery grafts after CABG,sudden death, stress-induced cardiomyopathy, coronary heart disease,heart disease and hypertension in patients with schizophrenia, panicdisorders triggering cardiac arrhythmias, vascular disease unsuitablefor vascular reconstructive surgery, improvement in blood flow aftersurgical grafting or other vascular surgery, reducing cardiac ischemiaand secondary ischemia-reperfusion injury, syncope, cardiac arrest,ventricular storm, channelopathies and conditions with short- or long-STsegments elevation or QT prolongation/dispersion includingcatecholaminergic polymorphic ventricular tachycardia (CPVT) and Long QTsyndrome. Not to be limited by theory, sympathetic denervation may alsoresult in improved lymphatic flow from the lungs and the heart and thusprovide symptomatic benefit in heart failure, hypertension (systemic,pulmonary, orthostatic), carotid sinus hypersensitivity, and pulmonaryedema through improved drainage or clearance of fluid from the lungs andthoracic cavity. While the sympathetic nerve supply to the lungs andheart is largely derived from the thoracic sympathetic chain bothdirectly and indirectly, many clinical researchers have shown thatprocedures targeted at the stellate ganglion alone (e.g. anestheticblock or surgical sympathectomy) may be sufficient to amelioratesymptoms of refractory angina or cardiac arrhythmias. For permanentprocedures, however, these patients run the risk of Homer's syndrome.Furthermore, delivery of a neurolytic agent there is particularlydangerous since the typical volume injected there, between 10-20 ml, hasbeen demonstrated to spread far from the site of injection.

Intrinsic cardiac. Atrial fibrillation may be suppressed by modulationof the sympathetic chain or the intrinsic cardiac autonomic nervoussyndrome (ICANS) embedded within the epicardial fat pads and theligament of Marshall (LOM). The four main ganglionated plexi (GPs) onthe atrium are the anterior right GP or right atrial (RAGP) at the rightsuperior pulmonary vein (PV)-atrial junction, the inferior right GP atthe junction of the inferior vena cava and both atria, the superior leftGP near the left superior PV-atrial junction and the left pulmonaryartery and the interior left GP at the left inferior PV-atrial junction.Different locations to stimulate, target, and ablate are described in,for example, U.S. Pub. No. 2005/0261672 to Deem et al., and Scherlag etal. (2009) which is hereby incorporated by reference in its entirety.

Other targets. Local delivery to heart. In some cases, the targeting ofthe intrinsic cardiac nervous system is desired. The intrinsic systemincludes parasympathetic, sympathetic, and interneurons. Local deliveryinto the epicardial fat pads containing these nerves may be desirable.Alternatively transvascular delivery of the therapy through the coronaryartery, great cardiac vein, or coronary sinus wall to the epicardialspace may be performed to deliver therapy around the externally facingside of the vessel. Alternatively, a region of one of these vesselscoursing across the epicardial surface of the heart may be used as asite to deliver the therapy to fill or partially fill the epicardial sacin order to achieve more widespread neuronal modulation or denervation.Similarly, adapting the devices used for intramyocardial delivery ofcells to deliver the neurolytic hydrogel to the anterior wall of theleft ventricle can in some embodiments be desirable, particularly sinceit is innervated by both the right and left cardiac sympathetic nerves.As with the paravertebral gutter, performing injections in and aroundthe left side of the heart first and then performing them on the rightside of the heart as necessary, may reduce the likelihood of arrhythmiasor other adverse events from flooding the tissue with so much agent. Insome embodiments, it is desirable to only denervate the left ventricle,and more specifically the anterior left ventricular wall.

Non Cardiac. Non-limiting examples of noncardiovascular indications fora long-duration or permanent therapy directed towards the lower cervicaland thoracic paravertebral space include, for example, facial flushing,upper (palmar, axillary, craniofacial) or lower extremity hyperhidrosis,complex regional pain syndrome types I and II, neuropathic pain, pre- orpost- or menopausal hot flashes, cancer-related hot flashes, suddenhearing loss, tinnitus, vascular insufficiency/occlusive vasculardisorders, intraarterial embolization and vasospasm, Raynaud's,spasticity, motor dysphagia including dysphagia relating to theproduction of speech, cerebral vasospasm, sleep quality, obstructivesleep apnea, hypokinetic (Parkinson's) and hyperkinetic movementdisorders (tremors, dystonia, chorea, tics, myoclonus, restless legsyndrome), lymphedema, neurogenic inflammation, hearing loss, cerebralischemia, cerebral vasospasm, cerebral embolism, subarachnoidhemorrhage, metabolic syndrome, obesity, sleep disorders, polycysticovarian syndrome, fertility hyperinsulinemia, hyperleptinemia, ulcersand acid reflux, idiopathic peripheral neuropathy, essential tremor,overactive bladder, testicular pain, knee osteoarthritis, cerebralpalsy, lower and upper limb spasticity particularly after a stroke,panic disorders, parotid dysfunction, temporomandibular disorder,idiopathic facial pain, pain from shingles, intractable chest wall painor oncologic thoracic pain, post-herpetic neuralgia, intractableitching, post-traumatic stress disorder (PTSD), memory dysfunction, poorlymphatic drainage and local edema of the upper extremity, as occursafter mastectomy other procedures involving surgery/radiation thatdisrupt the lymphatics, phantom limb pain, critical limb ischemia,amputation stump pain, pain following mastectomy, Bell's palsy,orofacial pain syndrome including neuropathic orofacial pain, vascularheadache and sympathetically maintained headaches, neuropathic painsyndromes in cancer pain, sudden infant death syndrome, endometrialand/or peritoneal pain, anorexia nervosa, thoracic outlet syndrome,arthritis, posttraumatic sympathetic dystrophy, thromboangitisobliterans, diabetes and insulin resistance, particularly at earlystages, collagen disease such as scleroderma, ischemic stroke andsubarachnoid hemorrhage. Sympathetic denervation may also be beneficialin, for example, the treatment of inflammatory diseases or diseases withan inflammatory component such as acute inflammation, shock(hypovolemic, septic, neurogenic), sepsis, and acute respiratorydistress syndrome by reducing neutrophil and natural killer cell countsand improving lymphatic flow, glaucoma, facial blushing of hyperhidrosis(T1 to T3, or T2 only), palmar hyperhidrosis (generally T2-T3), axillaryhyperhidrosis (generally T2-T4), reflex sympathetic dystrophy or complexregional pain syndrome, dry eye or mouth disorders, ischemic or diabeticulcers, limb ischemia or leg pain, vasospastic disorders, causalgia,peripheral arterial disease or occlusive arterial disease, burning painaccompanied by hyperpathia, hyperaesthesia, andhypercoagulative/prothrombotic states. In some embodiments, endpointsinclude, at least an amelioration of the symptoms associated with thepathological condition afflicting the host, where amelioration is usedin a broad sense to refer to at least a reduction in the magnitude of aparameter, e.g. symptom, associated with the pathological conditionbeing treated. In some embodiments, the endpoint can be reduction in asymptom such as anxiety and/or panic. In one embodiment, the treatmentof hot flashes results in a reduction in mean hot flash scores andfrequencies, such as measured by the Hot Flash Related DailyInterference Scale for example. Within these diseases, targeting of thestellate ganglion alone may be sufficient for treatment of CRPS (type Iand II) of the upper extremities, chronic and acute vascularsufficiency, occlusive vascular disorders of the upper extremities, poorlymphatic drainage, edema of the upper extremity following breastsurgery, post-herpetic neuralgia, sudden hearing loss, hyperhidrosis,Bell's palsy and orofacial pain, trigeminal neuralgia, vascular headachesuch as cluster and migraine headaches, phantom limb pain or amputationstump pain.

Hyperhidrosis. To date, the clinical focus of sympathetic chaindisruption procedures has been the treatment of hyperhidrosis throughthe denervation of palmar and axillary sweat glands. The second thoracicganglia (T2), and to a lesser extent the third thoracic ganglia (T3),innervate the eccrine sweat glands of the upper limbs. The fourth andfifth ganglia (T4, T5) innervate the eccrine sweat glands of the axilla.Of note, some groups have demonstrated that only a few T2/T3 fibersinnervate the hands whereas fibers from T4 pass through T2 and T3 toinnervate the hands and that T3/T4 fibers are the main source ofinnervation of the arm. Directing the therapy as described hereintowards these levels can provide a more safe and permanent treatment ofsevere hyperhidrosis than a VATS-based procedure.

Long duration blocks for other applications. Long duration blocks, inwhich the therapy includes the delivery of a sustained or controlledrelease formulation of anesthetic in the hydrogel, can be administeredto achieve a long-lasting block of the abdominal, thoracic, or lumbarlevels. At the thoracic paravertebral gutter, the therapy can provideanesthesia for chest wall incisions, drain sites, and parietal pleuraincluding the use of long-duration paravertebral blocks can be performedfor breast surgery including axillary dissection, VATS surgery,minimally invasive cardiac surgery, and open thoracotomy. Not to belimited by theory, the use of thoracic paravertebral block can reducecancer recurrence compared to other methods of anesthesia in patientsundergoing mastectomy and therefore the therapy may be delivered tothese patients. For abdominal surgery, the therapy can be administeredbilaterally in some cases and can be performed prior to, in conjunctionwith, or after the procedure, as necessary. The therapy can be deliveredto the lumbar plexus or the lumbar plexus-lower thoracic paravertebralgutter for anesthetic purposes prior to renal surgery, open andlaparoscopic cholecystectomy, appendectomy, inguinal hernia repair, andthe like.

Chronic pain management. Long-duration or permanent therapy directedtowards the paravertebral gutter (including cervical, thoracic, andlumbar) can be used for the treatment of chronic pain, particularlyvisceral pain. Given the recent discoveries that visceral and somatichypersensitivity may be related to the activation of adrenergicreceptors on sensory nerves (as well as transient receptor potentialchannels, opioid and cannabinoid) in addition to efferent nerves, thecontributions of sympathetic nervous system to aberrant pain signals areincreasingly appreciated. In some embodiments, therapy is delivered tothe paravertebral gutter for the treatment of visceral, chronic orneurogenic pain including but not limited to fibromyalgia, complexregional pain syndrome, pain from mesothelioma, post-thoracotomy chronicpain, pancreatitis, gastrointestinal tract neuroinflammatory disorderssuch as irritable bowel syndrome (IBS), irritable bowel disease (IBD),ulcerative colitis, and Crohn's disease.

CNS. As a result of reduction in systemic sympathetic vascular tone andalso possibly cerebrovascular tone and cerebrovascular vasospasm afterischemic or hemorrhagic injury, systems and methods as disclosed hereinmay be used to treat ischemic stroke and other neurological diseaseswhere cerebral blood flow constrictions or ischemia are implicated suchas migraine, headache and traumatic brain injury. In some embodiments,systems and methods may also be used to reduce the occurrence ofischemic stroke since cerebrovascular disease is often closelyassociated with cardiac disease. Similarly, modulation of thesympathetic nervous system can be used to modulate the release ofanti-clotting agents, such as tissue plasminogen activator (TPA) intothe blood.

Other organs. As with renal denervation, sympathetic chain denervationmay have a similar beneficial impact on many other visceral organs.Ablation of the cervical, thoracic, cervicothoracic, and lower thoracicchain has been demonstrated to have direct or indirect (reduction insystemic norepinephrine, for example) benefits on non-target organs andpathophysiology. In particular, neuromodulation of the upper thoracicand cervical sympathetic chain modulates angiotensin II levels and thusthe renin-angiotensin system (RAAS) and can be beneficial in thetreatment of acute or chronic kidney disease and renal failure. Thus,the therapy can result in improvements in, for example, renal, adrenal,liver, pancreas, spleen, gastrointestinal, and biliary disorders.

Neuromodulation for neuronal survival and/or regeneration. Forneuromodulation disorders such as postural syncope syndromes,attributable to disordered neural circuitry control, the therapy can bedelivered to the paravertebral gutter, particularly the upper thoracicparavertebral gutter to increase the survival and/or neurotransmissionin the sympathetic nerves. Many of these diseases are associated withneuronal cell death and reductions in norepinephrine in visceral organs.Neural degenerative diseases of the brain (e.g., Shy-Drager syndrome andParkinson's disease) which impair the central control of reflexsympathetic outflow, and peripheral sympathetic nerve degeneration (pureautonomic failure) or accompanying long-standing diabetes, posturaltachycardia syndrome (POTS) with an exaggerated reflex sympatheticnervous response to standing, as well as chronic fatigue, baroreceptorfailure, fibromyalgia, diabetes and diabetic neuropathy, multiple systematrophy, PKU, seizures, epilepsy, dementia and neurocardiogenic(vasovagal) syncope may be targeted with a local delivery ofneurostimulatory, neurosurvival, neuroprotective, or neuroregenerativeagents in a controlled release formulation, preferably a gel.

Other targets. Non autonomic related. The control afforded by deliveringneuromodulatory agents, for example, in a hydrogel permits the deliveryof the therapy to other autonomic and non-autonomic (somatic) ganglia,plexi and nerves generally. The therapy in some embodiments permits thereduction in the local dose administered improving both efficacy, localand systemic safety.

Other targets. Local delivery for pain management. The therapy may alsobe delivered locally to nerves for the amelioration of symptoms relatedto peripheral neuropathies. A neurolytic agent delivered in a gel can bepreferred in some embodiments since allows for reduction in the volumeof agent delivered as 1) the drug can remain in contact with the nerve(ganglia, plexus, nerve fibers) at a neurolytic concentration for longerthan an agent that washes over the nerve and spreads elsewhere. In oneembodiment, the stellate ganglion block is performed with 1-3 ml ofneurolytic/anesthetic agent in a gel as opposed to the 5-20 ml ofanesthetic delivered today which is well documented to travel to manyother off-target neural structures. Similarly, in one embodiment 5 to 10ml of the therapy is delivered to the celiac plexus instead of the 10-30ml of alcohol that is injected in the region today. This cansignificantly reduce the spread of a toxic agent through theretroperitoneum and potentially result in longer relief of symptoms.Other target tissues for the therapy include, but are not limited to thecarotid sinus, the superior laryngeal nerve, the petrosal ganglia, thenodose ganglia, the glossopharyngeal afferents from the carotid body andcarotid sinus, superior hypogastric plexus, ganglion impar, trigeminalganglia, subarachnoid space, epidural space, carotid sinus nerves,celiac plexus, celiac ganglia, retroperitoneal nerves, neuroma,splanchnic nerves, splanchnic ganglia, aorticrenal ganglia and anyganglia or plexi lying in and around the aortic arch and descendingaorta, pterygopalatine ganglion, and ciliary ganglion. Other targetsinclude any of the locations that anesthetic blocks are placed currentlysuch as the brachial plexus, retrobulbar, hypogastric plexus, nervesinnervating the pectoral and serratus anterior, transversus abdominis,saphenous nerve, femoral nerve, blocks at elbow and arm, axillary block,infraclavicular block, suprascapular and axillary nerve block,supraclavicular block, interscalene block, and endoscopic ortransabdominal blocks, or blocks for neuropathy. In particular,denervation of the nodose ganglia can be of particular interest sincethe ganglia play a key role in mediating cardiopulmonary andbaroreceptor information and given the close proximity to other neuralstructures, delivery of a neurolytic agent in a gel can be desirable tocontrol the spread of the neurolytic agent.

Identifying High Risk Refractory Angina/Ischemia Patients.

In some embodiments, high-risk patients can be qualified for receivingthe therapy through coronary angiography, fractional flow reserve (FFR)assessment (with, for example intravenous or intracoronary adenosine) inwhich an FFR of 1.0 is normal or >0.94 or if the FFR is abnormal.Similarly, patients who are at high risk for arrhythmias are defined byHRS but are generally patients that have a previous myocardialinfarction and should be considered for receiving the therapy.

In another embodiment, a patient that responds to an equivalentanesthetic block is considered a potential responder for the therapy andqualifies for receiving the therapy. The block may be a stellateganglion block, an upper thoracic paravertebral block, a lower thoracicblock, or a lumbar block. In one embodiment the block is performed,providing local anesthetic to the region and providing verification thatthe patient is likely going to be a responder to the therapy, and thenthe patient receives the neurolytic agent—hydrogel. In anotherembodiment, the patient receives a block and then comes back 2-6 weekslater when the block has worn off and/or the symptoms have returned.

Procedural Responders.

Assessing regional sympathetic nerve activity pre-, intra- andpost-operatively allows identification of appropriate patients for thetreatment, intraoperative confirmation of successful neuromodulation orneurolysis, and post-operative measures of short and long-term efficacy,respectively. In one embodiment, non-organ specific peripheralmeasurements of sympathetic modulation are monitored as a proxy fororgan-denervation. In one embodiment, a pulse oximeter (a reflectancepulse oximeter) adapted for use on the palm. The difference betweenbaseline laser Doppler blood flow and post-surgery blood flow, an over200% increase in blood flow with an increase in palmar temperature of1.44 degrees. In another embodiment, a pulse oximeter is used to monitorthe perfusion index (PI) at baseline until the sympathectomy procedureand post-procedure. A successful sympathectomy is defined as a twofoldincrease in PI on the ipsilateral arm. The change in skin conductanceoccurs as early as 1 minute after transection of the chain.

In one embodiment, cardiac and pulmonary and/or cardiothoracic cavitynerves are assessed directly to assess the integrity of sympatheticnerve function to the organs. In one embodiment, a sympathetic nerve isstimulated with a current frequency of about 10 to 50 Hz and anamplitude of 0.1 to 20 mA to inhibit the action potential propagation ofthe nerve. Some stimulation parameters that can be used or adapted foruse herein can be found, for example, in U.S. Pub. No. 2008/0147137 A1,which is incorporated for reference herein in its entirety. Bystimulating at a high frequency, the afferent and efferent nerves may beblocked.

Another approach is to look at a modifications of conventional spectralHRV analysis permit calculations of low-frequency (LF) andhigh-frequency (HF) spectral power and their ratio (LF/HF) in thesympathetic modulation of patients with refractory angina. Cardiacsympathetic activity is measured indirectly by LF. However, increasedskin temperature and decrease in skin resistance, particularly at thedigits, as measured by increase in skin temperature measurements andthermography, increase in pulse amplitude (plethysmography), increasedpeak flow frequency in the radial and ulnar arteries, abolition ofsympathogalanic response, and absence of sweating are consideredindicators of sympathetic denervation.

For example, in a patient with refractory angina or evidence of cardiacischemia, if a patient has normal coronary angiogram but an irregularFFR, the patient undergoes the sustained neuromodulatory block orneurolytic sympathectomy described herein. In one embodiment, FFR isperformed during the procedure and there is an improvement in FFR pre-and post- the procedure as the coronary ischemia improves.

In another embodiment, in a patient undergoing catheterization for aprocedure, a stimulating electrode is used to stimulate and detectsignals and isolate the SNS. For example, these signals could bestimulated and subsequently recorded in the SA node or ganglionatedplexus until they are recorded.

Pre- and Post-Procedural Approaches to Measuring Sympathetic NerveActivity.

In another embodiment, patients undergo neuroimaging technology.Patients are placed in a GE Advance Scanner (GE) 6-18F-fluorodopaminewas infused intravenously for 3 minutes and dynamic scanning data wereobtained for thoracic radioactivity. By doing this pre- andpost-procedure, successful cardiac sympathetic denervation is indicatedby low concentrations of radioactivity in the interventricular septumand left ventricular free wall, at <5000 Bq/ml per MBq/kg and <4000Bq/ml per MBq/kg. In another embodiment Iodine-123metaiodobenzylguanidine scintigraphic (MIBG) assessment is performed,which reflects number of norepinephrine reuptake transporters in thetissue (heart, lung, or other organ) and is thought to be an indicatorof sympathetic innervation. In some diseases this is likely to be thecase, such as the demonstration through MIBG of the reinnervation of theheart after orthotropic cardiac transplant or in diseases with loss ofcardiac sympathetic innervation, as in Parkinson's. MIBG studieshighlight cardiac sympathetic nerve dysfunction irrespective of whetherdegeneration of the nerves results in lowered NE uptake or whether thesympathetic nerves are present but the NE uptake has been downregulated.Therefore, MIBG may be used not only to stratify patients at risk forvarious diseases (e.g. arrhythmias, cardiac arrest, stroke) but it canpotentially be used to guide which patients should receive a treatmentthat modulates the activity of the dysfunctional sympathetic nerves.

Cardiac transplant recipients do not demonstrate I-123 MIBG cardiacuptake when studied <6 months from transplantation. However, physiologicand biochemical studies suggest that sympathetic reinnervation of theheart can occur >1 year after transplantation.

Alternatively, regional sympathetic nerve activity can also be assessedby isotype dilution derived measurements of organ specificnorepinephrine spillover into plasma and studies have demonstrated adramatic and almost complete reduction in norepinephrine levels in theheart after orthotopic cardiac transplantation or the lung after lungtransplantation. These results can be benchmarked against patients whoreceived cardiac transplantation and contrasted with patients undergoingsurgical sympathectomy on the left and or right and left sides.

Endovascular.

Recordings from post-ganglionic sympathetic efferent nerves, whethermulti-unit or single-fiber recordings can be obtained from nervesinnervating the lungs and heart via an electrophysiology diagnosticcatheter placed in the placed in the pulmonary or bronchial arteries orveins, an intercostal vein or artery, the subclavian artery, thecoronary arteries or coronary sinus, or theazygous/hemiazygous/accessory vein. In some embodiments, a catheter canbe placed in the pulmonary artery or pulmonary artery trunk so that itcan make direct measurements from sympathetic nerves innervating theheart and lungs, preferably from the extrinsic cardiac plexi.

Indirect assessments of cardiac sympathetic nerve activity may also bederived from paravertebral subcutaneous sympathetic efferents as thereis a higher density of them there. In one embodiment, recordingelectrodes are inserted into the subcutaneous tissue on the patient'sback on either side of the spine (dorsum) to measure sympathetic nerveactivity. Experiments in dogs have demonstrated that these nerves firein synchrony with cardiac nerves.

Tyramine Infusion Sensitivity.

Tyramine can be infused IV at a rate of 1 mg/min for 10 minutes into asupine patient with a hilt tilted at 15-30 degrees. Blood samples aredrawn at baseline and 10 minutes during the infusion and assayed forcatecholamine levels. Tyramine is a sympathomimetic amine and infusionwill increase cardiac contractility (impaired inotropic response) inpatients with intact cardiac sympathetic innervation but not patientswith cardiac sympathetic denervation. Sympathetic nerves take uptyramine via the norepinephrine transporter which enters the axoplasmand then is taken up into vesicles via the vesicular monoaminetransporter and in doing so, displaces norepinephrine into the axoplasmwhere it is deaminated to form dihydroxyphenylglycol. A portion of thenorepinephrine is released into the extracellular fluid and binds toadrenoceptors on cardiac smooth muscles cells resulting in inotropiceffects. Thus, attenuation of cardiac inotropic response to tyramineprobably reflect decreased vesicular norepinephrine stores and issuggestive of a successful procedure.

Isoproterenol Infusion Sensitivity.

Patients with cardiac sympathetic denervation have exaggerated responsesto isoproterenol, a beta-adrenoceptor agonist, possibly as a result ofbeta-adrenoreceptor upregulation/super sensitivity. On a separate day,isoproterenol was infused in 10 patients at four incremental doses of3.5, 7, 14, and 35 ng/kg/min for 10 min each until the heart rateincreased by 25 bpm from the baseline. Stroke volume, cardiac output,velocity index, acceleration index, pre-ejection period, leftventricular ejection time and electromechanical systole were measurednoninvasively using the BioZ impedance cardiographic device, before andduring the infusions. Total peripheral resistance and LVET index and PEPindex, systolic time ratio and systolic time ratio index werecalculated. A pattern of prolongation of PEP and shortening of LVETcharacterize myocardial infarction, angina pectoris, and heart failure.Thus patients who have undergone a successful procedure will haveevidence of denervation supersensitivity within a week of theirprocedure, as evidenced by exaggerated cardiac responses toisoproterenol.

Non-limiting examples of tissues and vessels that can be targeted withsystems and methods disclosed herein is listed below, as well aselsewhere herein.

Paravertebral space. The thoracic paravertebral space (TPVS) is awedge-shaped (triangular) space that lies on either side of the thoracicvertebral column (vertebrae) at a given level that contains loose fattytissue. FIG. 2A is a horizontal section highlighting various anatomicalfeatures in the thoracic region. Anteriorly or laterally the TPVS isbounded by endothoracic fascia 524 and parietal pleura 514, posteriorlyit is bounded by the superior costotransverse ligament 518, and mediallyit is bounded by the posterolateral aspect of the vertebral body 522,the intervertebral disc and intervertebral foramen. Medially, the spaceis in communication with the epidural space via the intervertebralforamen. However, the continuity between the paravertebral and epiduralspace, particularly in older patients, is a subject of controversy.Laterally, the space communicates with the intercostal space, throughwhich the intercostal artery 506, vein and nerve 516 (and accessoryvessels) travel. The space is separated from the space above and belowby the heads and necks of adjoining ribs. There is bilateralcommunication between the paravertebral spaces 500, 500′ on either sideof the vertebral column via the prevertebral and epidural space. Theparavertebral gutter (shown cross-hatched: right 500′, left 500) is thecontinuous channel that connects adjacent paravertebral spaces to oneanother on either side of the vertebral column via the prevertebral andepidural space. The paravertebral spaces extend from the first rib(stellate/T1 sympathetic ganglia) to the sacrum although it is dividedinto the thoracic paravertebral gutter space and the lumbar space,divided by the psoas muscle. The cervical stellate ganglia is contiguouswith the paravertebral space as contrast injected there readily travelsin the paravertebral gutter. Also illustrated herein is the descendingaorta 508, azygous vein 504, accessory hemiazygous vein 510, sympatheticganglia 502, right lung 513, left lung 512, spinal cord 520, andvisceral pleura 515. FIG. 2B is a close-up view of FIG. 2A illustratingselected structures illustrated in FIG. 2A in or in proximity to theparavertebral gutter 500 (shown cross-hatched).

The TPVS space contains neural structures including the spinal(intercostal) nerve 516, the white and grey ramus communicans, thesympathetic chain 502, the dorsal/posterior and anterior/ventral ramusor divisions of the somatic nerves, the intercostal nerve and the ramicommunicantes as well as vessels including the intercostal artery andvein. The intercostal nerve 516 in this region includes the proximalpart of the posterior division as well as the rami communicantes of theintercostal nerve 516. In this region, the sympathetic chain coursesvertically over the heads of the ribs, just lateral to the radiateligaments (Vallieres 2007). Also, the spinal nerves emerge from theintervertebral foramen and give off a dorsal and ventral ramus withinthe TPVS.

The paravertebral space can be further subdivided into an anterior(anterolateral extrapleural) space containing the sympathetic ganglia502 and a posterior (posteromedial subendothoracic) compartment by thethin endothoracic fascia 524. In some embodiments, injections into themore anterior compartment can result in better longitudinal spread upand down the paravertebral gutter 500, 500′ as well as more consistentanesthetic paravertebral blocks.

Intervertebral Foramen.

The intervertebral foramen protects the spinal ganglion and nerve roots,include the dorsal root ganglion as they exit the spinal cord. Theforamen also protects the branches of the spinal arterial and venoussystems.

Rami Communicantes.

Between one and nine or more anterior/dorsal rami come off of thethoracic sympathetic ganglia and/or chain within the paravertebral spaceand course directly to either the adjacent intercostal nerves or to thethoracic organs. The rami that travel directly to the lung and heartcross anteriorly or posteriorly over or across one of several greatvessels in the thorax. 1) On the right side, rami from the cervical andthoracic sympathetic chain cross over the azygos vein and the arch ofthe azygos vein as it courses over the rostral aspect of the lung hilum.2) On the left side, the cervical and upper thoracic rami cross over theaccessory hemiazygos vein (or more caudally the lower thoracic crossover the hemiazygos vein) and may cross over the communicating vein thatruns between the hemiazygos and azygos veins and along or around theintercostal veins. 3) On the left and right side, rami from the cervicaland thoracic sympathetic chain cross posteriorly and/or anteriorlyacross the aorta and the arch of the aorta to the heart and lungs. Forexample, some of the rami from the upper thoracic and cervicalsympathetic chain travel directly to the superficial and deep aorticplexus under the aortic arch and on the aorta. A portion of the rightand left sided rami run along and/or around the intercostal arteriesmedially from the sympathetic chain back to origin of the intercostalarteries origin at the aorta and on to the heart and lungs. Some of thefibers also course rostrally and caudally around and along the aorta onto other plexuses, ganglia, and internal organs. 4) The rami may travelfrom coursing along one or more intercostal arteries to follow thebronchial arteries into the lungs. The posterior bronchial arteries, forexample, travels across the posterior aspect of the bronchi. Theafferent and efferent fibers may enter the lung around and along thebronchial vessels. In particularly, these bronchial vessels coursethrough or alongside the posterior and anterior pulmonary plexus. 5)Lastly, they may cross the thoracic duct and the esophagus.

Intercostal Nerves.

Intercostal nerves are located bilaterally on the anterior rami of theupper eleven thoracic nerves. Each nerve gives a white branch to andreceives a grey branch from a ganglion of the sympathetic trunk. Theanterior nerve root enters the corresponding intercostal space as theintercostal nerve where it travels laterally to join the intercostalvessels in this space. At the angle of the ribs the intercostal nervespass into the interval between the external and internal intercostalmuscles. This neurovascular bundle runs forward between the muscles, toabout the mid-axillary line. Then the intercostal nerve begins to passobliquely through the internal intercostal muscle and emerges on theinterior surface at the junction of the bone with the cartilage of therib. From here, the nerve continues medially and is found between theinternal intercostal muscle and the pleura in the case of the first twonerves and between the internal intercostal muscle and the transversusthoracis in the case of the third, fourth and fifth nerves. Theintercostal nerve usually typically comprises three or four smallbundles without any single enclosing fascial sheath. The nerve bundlescross the paravertebral space and make their way to posteriorly to thesubcostal groove, the triangular space bounded by the rib, the posteriorintercostal membrane and the internal intercostal muscle. This groovehas an area of about 0.75 cm² and is largely filled with fat. Generally,the first two thoracic nerves supply the upper extremities and theirthoracic branches supply the thoracic chest wall. The lower fivethoracic nerves supply the chest wall and upper abdomen. The second tothe sixth intercostal thoracic nerves and a small branch from the firstthoracic intercostal nerve supply the chest wall.

Intercostal Artery.

In the uppermost two intercostal spaces, the intercostal arteries rundorsoventrally and are derived from the superior (supreme/highest)intercostal artery which is a division of the costocervical branch offof the subclavian artery. These arteries cross the left superiorintercostal vein.

From the third (or fourth) thoracic level down (referred to as the lowernine levels), each vertebral level contains a pair of segmental arteriesthat arise from the posterior aspect of the descending aorta and arecalled the right and left (posterior) aortic intercostal arteries. Sincethe aorta lies on the left side of the vertebral column, the rightaortic intercostal arteries are longer than the left and cross over thevertebrae behind the esophagus, thoracic duct and azygos vein. On theleft side, the intercostal arteries are crossed by the hemiazygos vein.Both intercostal arteries run along the anterolateral surface of eachside of the vertebral body and divide into a dorsal/posterior branch andventral/anterior branch near the posterior aspect of the body, anteriorto the neural foramen. Prior to the bifurcation, the arteries arecrossed by the sympathetic trunk at the rib head. The vessels arecovered by pleura. The dorsal branch travels posteriorly with thecorresponding dorsal ramus of the spinal nerve and crosses below thetransverse process, medial to the superior costotransverse ligaments.The ventral branch of the segmental artery becomes the (aortic)intercostal artery which runs laterally and inferiorly to the subcostalgroove between the interior and exterior intercostal muscles near theposterior angle of the rib.

From the angles of the ribs onwards to a point midway between thevertebral column and the sternum, the aortic intercostal arteries lieunder shelter of the notched lower margins of the ribs (subcostalgroove) which bound the spaces superiorly. In this area, the intercostalvein is typically superior to the artery and both are superior to theaccompanying nerve. However, there are significant inter-levelvariations and patient variability in the relative arrangement of thevessels with respect to the nerve.

The posterior intercostal arteries measure about 1.5 mm (range 1.0 and2.2 mm) in the 2^(nd) intercostal space at their rib angle and areapproximately 0.8 mm in outer diameter at the mid-axillary line. Thediameter of the posterior intercostal artery increases down the thoraxfrom 1.5 to 4.3 mm. The vascular bundle as a whole measures between 1.6to 3.7 mm. There are collateral intercostal arteries which originatefrom the posterior intercostal artery at an angle of 45 to 60 degreeswith it. The point of origin is between the vertebral body and thecostal angle of the inferior border of the rib.

Intercostal Vein Anatomy.

The venous drainage of the vertebra and thoracic costovertebral arealargely parallels the arterial blood supply. Right. On the right side,the first intercostal vein passes to the right brachiocephalic vein(right innominate vein). The second, third and fourth (posterior)intercostal veins drain into the right superior intercostal vein andthen to the azygos vein which is located on the medial side of thefourth or fifth rib head. The fifth through the ninth intercostal veinsdrain directly into the azygos vein. Occasionally, the fourthintercostal vein drains together with the fifth through the ninthintercostal veins to the azygos instead of the right superiorintercostal vein. The size of the superior intercostal vein increases asthe vein nears the azygos vein. Of note, the right side the secondthrough fourth intercostal veins widen appreciably as they drain to thesuperior intercostal vein at the rib head, as illustrated in a diagramof the third and fourth levels. Left. On the left side, the upper threeor four intercostal veins unite and drain into the left superiorintercostal vein, which drains into the left brachiocephalic vein at thelateral side of the rib head. Occasionally the first intercostal veinwill drain directly into the left brachiocephalic vein. There may be acommunicating branch from the left superior intercostal vein to theaccessory hemiazygos system. The fifth through eighth intercostal veinsdrain into the accessory hemiazygos vein and then to the azygos vein.Anatomical variability results in the fourth intercostal veinoccasionally draining into the accessory hemiazygos instead of the leftsuperior intercostal vein. There may be a vessel communicating betweenthe fourth and fifth intercostal veins thereby connecting the superiorintercostal and accessory hemiazygos systems. On the left side, theintercostal vein size generally does not increase in size as the riphead and drains into the left superior intercostal vein.

The intercostal arteries and veins may pass anterior or posterior to thesympathetic trunk. Generally, the majority of intercostal veins passposteriorly with the exception of the first intercostal vein. Similarly,the majority of aortic intercostal arteries pass posteriorly to thesympathetic trunk with the exception of the two intercostal arteriesarising from the superior intercostal artery.

Intercostal veins vary tremendously in size, and are generally larger onthe right than the left side of a patient. For example, in the third andfourth intercostal spaces, large veins are found in 36% and 68% ofpatients, respectively, on the right side. On the left side, only 2% and5%, respectively, of the third and fourth intercostal veins are large.There is also variability in the size, presentation and location ofanterior crossing intercostal veins, again, with these veins found onorder of 15-30% of time on the right side but rarely on the left side.

Bronchial Arteries.

Bronchial arteries are systemic vessels bringing oxygenated blood fromthe descending aorta to the lung and bronchial tree.

Carrying less than 4% of the total cardiac output, bronchial arteriescan be interrupted without causing any obvious dysfunction. Thesearteries appear to play a major role in the vital airway defenses, fluidbalance, and metabolic function of the lung. In response to injury,these vessels can enlarge and may assist or take over the gas exchangefunction if the pulmonary function fails in any region of the lung. Theydecrease edema formation after ischemia and reperfusion and contributeto lung lymph flow.

More recently, the circulation, and the bronchial circulationspecifically, is thought to play an important role in the pathogenesisof inflammatory airway disease. The bronchial circulation receives onlyabout 1% of the cardiac output in health but serves an important role inmaintaining airway and lung function. In disease, the bronchialcirculation can increase in size to provide lung parenchymal perfusionwhen the pulmonary circulation is compromised. Bronchial blood flow isincreased in patients with asthma (and not COPD) and is thought to bethe result of a combination of angiogenesis and plasma leak.

The bronchial arteries originate orthotopically from the anterolateralaspect of the descending aorta between the level of T5 and T6. Morerarely, they may also arise from the aortic arch or an aortic vesselcollateral. There are rarely more than four ostia and the farthest apartaverages 18 mm.

Right bronchial artery. Typically, one right bronchial artery arisesfrom the first right aortic intercostal artery and courses to the lung(5 to 8.5 cm). Alternately, the right (superior) bronchial artery mayarise from the thoracic aorta directly, from a common trunk to the rightthird (posterior) intercostal artery, the subclavian artery, the leftsuperior bronchial artery or another right intercostal artery. Duringits course, the right bronchial artery typically lies with theintercostobronchial artery along the right anterolateral aspect ofthoracic levels T3-T4 and then passes anteriorly on the right of thethoracic duct, crossing the esophagus from back to front and right toleft before ending at the level of the main bronchus. The artery runsparallel to the arch of the azygos vein and the lymphatic vessels. Thebronchial artery gives branches to the midportion of the esophagus, thetrachea, the pericardium, the left atrium, and the mediastinal lymphnodes. The artery is especially close to the vagus nerve, which itcrosses and with the branches of which it often intermingles. Thebronchial artery branches to the visceral pleura and other mediastinalstructures including the esophagus, hilar and peritracheobronchial lymphnodes, and the heart. The arteries are around 1.5 mm in diameter. Theartery may be closely associated with the cardiopulmonary nerves arisingfrom the right stellate ganglion and may serve as an extension of thesympathetic cardiopulmonary nerves to the heart and lungs.

Left bronchial artery. There may be one or two left bronchial arteriesthat have a shorter course to the lung than the right bronchial artery(2 to 4.5 cm). These arteries arise from anywhere over the right andleft anterolateral aspect of the aorta. In up to 50% of cases, there maybe a common trunk giving rise to the right and left bronchial artery butit is not typically the only blood supply the lung (only supply in 2.5to 18.5% of cases). If there is a common trunk present, it runs onlybetween 1 and 1.5 cm before the bronchial arteries branch.

Furthermore, numerous accessory bronchial arteries are common and appearto be of ectopic origin. Occasionally these vessels provide appreciablebronchial arterial flow. They arise from the aortic arch or theipsilateral subclavian artery. On the right, where they are more common,they originate from the concavity of the aortic arch, the lower thoracicaorta and from the left subclavian artery or its branches.

Finally, there is especially dense innervation of a population ofarterioles arising at right angles from the pulmonary arteries which mayplay a key role in the distribution of blood flow in the lungs.

Pulmonary arteries. Fibers also travel across pulmonary artery to theanterior pulmonary plexus (also pulmonary ligament).

Pleura.

The pleura lines the inner surface of the chest wall. The pleura isimmediately adjacent to and covers the internal intercostal vessels,nerve, and ribs. Care should be taken not to significantly disrupt thepleura and thus cause a pneumothorax.

Target Nerve for Ablation within the Paravertebral Gutter orIntervertebral Foramen.

The target tissue may be, for example, any number of the following: theposterior/dorsal nerve root, the anterior/ventral nerve root, the dorsalroot ganglion, the sympathetic cord or chain, the white ramuscommunicans, the grey ramus communicans, the sympathetic ganglion,dorsal root ganglion, the dorsal (primary) ramus/rami, the ventral(primary) ramus/rami, the intercostal nerve(s), the intrathoracic ramusbetween the first and second nerves or second and third nerves or ramithat directly extend to the brachial plexus, other unnamed ramicommunicantes that originate from the sympathetic ganglion/chain andtravel directly to the thoracic cavity, and unnamed rami communicantesthat originate from the sympathetic ganglion/trunk and travel to theintercostal nerves. The afferent or efferent fibers may be part of amixed fiber bundle, such as the white or gray ramus communicans.

Organ Targets.

In some embodiments, the therapy may target somatic motor, somaticsensory, sympathetic motor and/or sympathetic sensory fibers thatinnervate, for example, the following organs and tissues in the thoraciccavity: the trachea, right and left primary bronchi, right and leftupper/middle/lower lobar bronchi and bronchial tree, right superiorlobar bronchus/eparterial bronchus, hyparterial bronchus, esophagus,heart, thymus gland, the (parietal/visceral) pleura, pericardium,epicardium, diaphragm, thymus, transversus thoracis muscle, pectoralisminor/major, (superior/anterior/posterior) mediastinum, mediastinal fatpad, retrosternal fat pad, epicardial fat pads, lung root, lung hilum,lymph nodes including the tracheobronchial lymph nodes, bronchopulmonarylymph nodes, mediastinal lymph nodes (superior/central/posterior),diaphragmatic lymph nodes, left/right bronchomediastinal lymphatic trunkand posterior, left/right jugular lymphatic trunk, left, rightsubclavian lymphatic trunk, thoracic duct, the skin, the sweat glands,the diaphragm, and the peripheral vessels.

Indirect Nerve Targets.

As a result of modulation of the nerves in the paravertebral gutter, insome embodiments the therapy result in denervation of the followingvessels, both the innervation of the sympathetic fibers to the vesselsthemselves, as well as denervation of the fibers coursing along or overthese vessels to reach a distant target. These vessels include theascending/descending aorta, aortic arch, superior vena cava, internalthoracic artery and vein, pericardiophrenic artery, intercostal arteryand veins, musculophrenic artery and vein, superior phrenic artery andvein, right/left brachiocephalic vein, brachiocephalic artery, superiorepigastric artery and vein, right/left common carotid artery, azygosvein, hemiazygos vein, accessory hemiazygos vein, communicating veinbetween azygos and hemiazygos veins, supreme intercostal artery andvein, costocervical trunk (artery), internal jugular, external jugular,right/left subclavian artery, right/left subclavian vein, left/rightinnominate vein, right/left pulmonary arteries and branches thereof,right and left (superior/inferior) pulmonary vein, pulmonary trunk,anterior/posterior bronchial artery, bronchial artery branches from theaorta to the trachea, esophageal artery and vein, inferior thyroid vein,internal/external and left internal jugular vein, thyrocervical trunk,celiac trunk, cephalic vein, superior/inferior mesenteric artery,hepatic artery or veins, portal vein, splenic artery or vein, thymicvein, anterior cardiac artery/vein, right/left coronary artery,circumflex branch of left coronary artery, anterior cardiac branch ofright coronary artery, anterior interventricular branch of left coronaryartery, posterior interventricular branch of right coronary artery, andother coronary artery branches, great cardiac vein/left coronary vein,middle/small cardiac veins, posterior vein of left ventricle,interventricular vein, and coronary sinus. Alternatively, the therapymay be delivered transvascularly to denervate the nerves around thesevessels either on one or both sides of the vessel or circumferentially.

Similarly, modulating the nerves within the paravertebral gutter maydirectly or indirectly lead to denervation of the common carotid plexus,greater/lesser splanchnic nerve, inferior/superior cardiac nerve, ansasubclavia, nodose ganglion, superior cervical ganglion, middle cervicalganglion, inferior cervical ganglion or stellate ganglion orcervicothoracic ganglion, inferior cervical cardiac nerve, the recurrentlaryngeal nerve, celiac ganglion, aorticorenal ganglion, superiormesenteric ganglion, the right/left vagus nerve (some sympatheticafferent/efferent fibers are speculated to join these bundles inhumans), right/left phrenic nerve, esophageal plexus, posteriorpulmonary plexus, anterior pulmonary plexus, deep cardiac plexus,superficial cardiac plexus, intercostal nerve, pericardial branches ofthe phrenic nerve, the epicardial branches of the atrioventricularbundle/node, sinoatrial node, and ganglia innervating the atria andventricles. Alternatively, these ganglia and nerves may be targeteddirectly through a percutaneous, transcutaneous or endovascular routewith the assistance of ultrasound, fluoroscopic, or CT guidance.

Direct/Indirect.

Neuromodulation can be achieved via direct or indirect application ofenergy or neuromodulatory agents to target neural matter, to adipose orfascial tissue that contains the neural matter or to vascular structuresthat support or intersect the target neural matter.

In another embodiment, the neuromodulatory agent is delivered to thesympathetic pre- or post-ganglionic nerve or parasympathetic fibers asthey course through any number of the heart, trachea, bronchi, lungs,diaphragm, stomach, small and large intestines, colon, kidneys, ureters,bladder, liver, urethra, adrenal glands, omentum, gall bladder, ovaries,uterus, fallopian tubes, vagina, placenta, testes, epididymis, vasdeferens, seminal vesicles, prostate, salivary glands, esophagus,spleen, thymus, pancreas, and endocrine glands (pituitary, pineal,thyroid, parathyroid, adrenal), cornea, iris, ciliary body, lens,retina, outer, middle or inner ear, olfactory epithelium, and the lymphnodes, vessels, and ducts.

In another embodiment, the neuromodulatory agent is delivered locallyinto the lungs by intrapulmonary injection, pleural injection,intercostal space injection, peri-tracheal injection, peri-brachialartery injection, peri-pulmonary artery/vein injection. Specifically,the target region is the lung hilum in some embodiments. This region,containing the pulmonary vasculature and the bronchi, and is bounded bythe pleural sac, can be filled with the therapy by performingtransarterial injections of the therapy from the right and leftbronchial arteries in the region of the hilum. In another embodiment theneuromodulatory agent is delivered locally to the heart byintrapericardial, epicardial, epicardial fat pad, or intramyocardialinjection. In another embodiment, the neuromodulatory formulation isdelivered into the interstitial space surrounding the injured orischemic myocardium. In another embodiment the neuromodulatory agent isdelivered into the intrinsic pulmonary or cardiac plexi or the plexibetween the two.

Targeting of Specific Arm.

The therapy may be directly towards a purely efferent or afferent nerveswhether through spatial constraint of the delivery of the therapy to aspecific region, such as the anterior/ventral nerve root orposterior/dorsal nerve root, respectively, or through the delivery of aneuromodulatory agent that has preferential affinity or stronger effecton one type of nerves over another, such as for sympathetic efferentsover sympathetic visceral afferents. Alternatively, a mix of afferentand efferent fibers may be targeted as they run their course wrappinglongitudinally along a blood vessel to the thoracic organs or simplycrossing a blood vessel on their way to the thoracic organ. In someembodiments a specific neuron, soma, axon, or nerve fiber, nerveplexus/plexi or nerve bundle may be targeted. In addition, the methodsand apparatus described herein may, for example, be used to modulateparasympathetic nerves and/or the central nervous system including thebrain and spinal cord.

Terms for Neuromodulation and Energy Based Modalities.

Terms that describe modulation of the nervous system or neuromodulationrefer to providing excitatory, inhibitory, blocking signals to the nerveincreasing or decreasing the likelihood for an action potential, themodulation of the nerve to improve its survival or result in its celldeath, the stimulation of a nerve to regenerate, the stimulation of anerve to fire action potentials such as nerve stimulation, and/or resultin the up- or down-regulation of proteins including neurotransmitters,receptors through viral or non-viral vectors delivering DNA, RNA, siRNA,microRNA (miRs), modified messenger RNA, or antibodies.

Neuromodulation approaches to block, temporarily block, or eliminatenerves include, for example, nerve blockade or blocking, neuroablation,chemoablation, radiofrequency ablation, neurolysis, chemolysis, chemicalneuroablation, such as sympathicolysis. Alternatively, when a procedureto remove nerves is performed it may involve the followingterms—icotomy, -ectomy etc. such as sympathectomy or sympathicotomy orramisectomy. Neuromodulation can refer to chemical, mechanical, orelectrical methods to modulate nerve conduction. Electrical methodsinclude hyperpolarization block, cathodal, anodal, or collision block,as described for example in U.S. Pub. No. 2005/0228460 A1 to Levin etal., which is hereby incorporated by reference in its entirety.Overpacing or overstimulating a nerve (such as with a neurotransmitter,e.g. nicotine) may also induce a block by generating stimulating thenerve at a rate that exceeds its capacity to generate an actionpotential. In this manner, neurotransmitters stores are depleted and thenerve is temporarily unable to convey signals to other nerves andtissue.

The radiofrequency generator and catheter can have, in some embodimentsa closed loop element to measure impedance, deliver electricalstimulation (e.g. 2 Hz current for motor and 50 Hz for sensory) toconfirm the position of the electrode in the location of theparavertebral gutter as well as deliver ablative energy to arbitrarilyor selectively interrupt the sympathetic chain. In one embodiment,sensory stimulation is carried out at 50 Hz until a tingling sensationin the select dermatome noticed using a 0.4 to 1 V stimulus. It may alsobe possible to perceive muscle contractions (anterior root) at athreshold 1.5 times below the sensory threshold. In addition, the systemcan perform thermal lesioning with a preferably bipolar electrode with acontinuous and/or pulsed RF signal, and monitor the temperature at thetip of the device. In one embodiment, the RF energy is continuous,providing indiscriminate destruction of sympathetic afferents andefferents. Alternatively, the parameters of pulsed radiofrequency signalallow the targeted ablation of C-fibers. In one embodiment, a 100 mmcannula (Radionics SMK 22 G, 5 mm active tip) is inserted and advancedto the paravertebral space. The stylet of the cannula is replaced with aflexible RF probe with either a monopolar electrode at the tip orbipolar electrodes spaced, for example, 1-10 mm apart which is advancedthrough the paravertebral space up to the desired thoracic level, forexample from T4 up to T1, or up to the middle of the first rib.Alternatively, the catheter can be advanced rostrally one or two levels,the energy delivered, and then retracted and directed caudally where thecatheter then delivers RF at one or two levels.

In one embodiment, contrast is injected (e.g. iohexol) to confirm theappropriate positioning of the cannula and confirm an extravascularlocation and absence of intrathecal or intrapleural spread followed by 2ml of 2% lidocaine. The hydrogel formulation is then injected at thedesired target levels. The hydrogel, such as the in situ crosslinkedPEG-based hydrogel, has enough mechanical integrity to allow a catheterto move through them without collapsing. A flexible RF probe with athermocouple electrode is advanced to the target region through thehydrogel. In this case, the hydrogel has created a potential spacethrough which to deliver the RF energy with less concern for inadvertentperforation of the pleura. The RF probe may utilize a local coolingmechanism, such as a balloon, to prevent local destruction of thehydrogel where the highest temperatures are present (e.g. melting).Destruction of the ganglia and nerves within the paravertebral gutteroccurs between 60° C.-up to 75° C. or more.

In another embodiment, saline (with or without contrast) is deliveredthrough a catheter to fill the paravertebral gutter and to push thepleural membrane away from the sympathetic chain. The steerable RFcatheter is advanced up or down the paravertebral gutter and energydelivered at appropriate intervals to destroy the sympathetic chain,sympathetic ganglia, and rami communicantes. In another embodiment, theadvancing front of the RF catheter has a saline port that allows for amoving from of expansion of the pleura to create the potential spacewithin the paravertebral gutter through which the catheter can advancesafely. In another embodiment, the RF catheter has side ports thatcontinuously deliver saline around the catheter tip and shaft to allowit to advance safely within the paravertebral gutter.

The probe may include continuous or overlapping probes (4 to 10 mm probeapproximately 10 mm apart), both of which, with the appropriate spacing,can generate a contiguous lesion. Burns can then be performed inapproximately 2-5 minutes with a cooling catheter. Radiofrequency isdelivered at a frequency of 500 kHz and a power of 1-50 Watts for adefined period of time, for example 1-30 minutes, preferably 1 to 5minutes. Several embodiments using low-dose radiofrequency ablation,such as those delivered to ablate target nerves within and alongside theadventitia of the renal arteries to treat hypertension, may beapplicable. For example, ramped low power RF energy (5 to 8 watts) for aselect period of time (2 minutes) may be desirable (as disclosed, forexample, in U.S. Pub. No. 2011/0207758 A1 which is hereby incorporatedby reference in its entirety). Various embodiments of methods,apparatuses, and systems for performing renal nerve ablation aredescribed in greater detail in U.S. patent application Ser. No.12/545,648, filed Aug. 21, 2009 and PCT/US09/69334, filed Dec. 22, 2009,both of which are incorporated herein by reference in their entireties.In one embodiment the energy is delivered circumferentially and inanother embodiment the electrodes and the catheter can be biased todirect the energy in one direction, such as posteriorly.

Cryotherapy

In another embodiment, a cryoballoon or probe containing internallycirculating liquid nitrogen can be similarly delivered within theparavertebral gutter as the RF system embodiments, except that thetemperature between 0 to −200° C. (e.g. adaptation of CardioCryotechnology).

Microwave energy delivered in the range of 0.9 to 2.4 GHz at a power of1-100 Watts applied through monopole, dipole, half-dipole, or helicalcoil antenna.

Ultrasound.

The ultrasound transducer may range from 0.1 to 10 mm, more preferably0.1 to 3 mm, more preferably less than 1 mm. At this range, frequenciesfrom 2 MHz to 15 MHz may be employed, more preferably 5 to 10 MHz, morepreferably 7 MHz. Using this range of frequencies, the transducer may befocused at a distance less than 25 mm, preferably less than 10 mm, morepreferably less than 5 mm, more preferably 2-3 mm away. Overalltransducer surface area may be 1 to 50 mm², more preferably 12 mm².Acoustic power may be around 1 Watt. The transducer may be a cylindricaltransducer curved about its longer dimension, a cylindrical transducercurved about its shorter dimension, a concave transducer curved alongthe shorter dimension, or a flat transducer. An ultrasound transducermay also be employed that uses an inflatable membrane and soliddiffraction lens. Multiple transducers with different focal lengths maybe employed.

Minimally Invasive Optics.

In some embodiments optical fibers with a light source for illuminationof the paravertebral gutter may be employed with these devices.

Catheter Based Transmural RF Delivery.

In one embodiment, a balloon flexibly and irregularly expands to conformto the vessel wall, such as a vein, particularly in regions where thevein is bifurcating and the ostia are irregularly shaped and sized. Theballoon has cooling fluid in it to protect the vessel wall and anatraumatic tip on the balloon guide avoids damage to the vessel ortrauma to the pleura.

Electromagnetic.

Paramagnetic nanoparticles or microparticles can be delivered to theregion surrounding the sympathetic chain and then heated with anexternal electromagnet to ablate the nerves (ApexNano Therapeutics,Israel).

Insulated Tips.

A steerable cannula with a tapered tip can be placed at the targetlocation. The cannula can have smooth tapered siliconized ornon-siliconized insulation with tip exposures of 2, 4, 5, and 10 mm, orup to 20 mm. The tip may be straight, curved, and sharp, or blunt.

Nerve tissue may be decreased, partially or completely destroyed orremoved, denervated deactivated, or down-regulated. Nerve tissue mayundergo necrosis, apoptosis, atrophy, gene expression down or upregulation, protein expression down or up regulation, ablation. Withsome approaches, the entire nerve may be destroyed and in otherapproaches, specific regions of the nerves may be targeted such as theganglia or soma, the axons, and/or the nerve terminals.

Intravascular Device Energy Modalities.

In some embodiments, the neuromodulation may be achieved from an intra-to extravascular approach via an endovascularly placed device inproximity to the target neural matter or through a percutaneousparavertebral approach. In some embodiments, the therapy can bedelivered from an anterior approach directed towards the stellateganglion and the top of the TPGS. Alternatively, an anterior approachsimilar to that of the approach to the stellate ganglion but withsubsequent guidance-based navigation to the top of the paravertebralgutter, may be desired. In this manner, the therapy can be deliveredfrom the top of R1 down to the desired target level directly. In somecases, the therapy is delivered from one injection site to multipleparavertebral levels, in contrast to other approaches that ablate onlyone level at a time, such as described, for example, in U.S. Pub. No.2013/0296646 to Barbut et al., which is hereby incorporated by referencein its entirety.

Generally, the neural modulation may be achieved in some embodimentsthrough electrical, thermal (heating or cooling; resistive or infrared),mechanical, or chemical energy. The energy delivery device can belocated in or otherwise associated with the catheter and emits energyfrom the catheter. The energy delivery device may be located in a needletip and energy is emitted from the needle in some cases. An energydelivery device such as, but not limited to, high voltage field pulses,direct current, monopolar radiofrequency (such as described, forexample, in U.S. Pat. No. 8,175,711 to Demerais et al., incorporated byreference herein in its entirety), bipolar radiofrequency, pulsedradiofrequency, high-intensity focused ultrasound (HIFU)(continuous,pulsed) (such as described, for example, in U.S. Pat. No. 8,206,299 toFoley et al., incorporated by reference herein in its entirety),low-intensity focused ultrasound (LIFU), nonfocused ultrasound, otherforms of ultrasound, microwave, laser, steam or hot water, coldradiation, cyrotherapy, optical, light, phototherapy, X-ray or radiationtherapy (such as described, for example, in U.S. Pub. No. 2013/0035682to Weil et al., which is hereby incorporated by reference in itsentirety) magnetic, electromagnetic, plasma, reversible or irreversibleelectroporation, lithotripsy (extracorporeal, intracorporeal,extracorporeal shockwave therapy), vibrotactile, kinetic, potential,pressure, nuclear, elastic, and/or hydrodynamic energy (as outlined, forexample, in U.S. Pub. No. 2013/0204068 to Gnanashanmugam et al., whichis hereby incorporated by reference in its entirety). The mechanicaldevice may perform, for example, cutting, sealing, ligation, orclipping.

These energy modalities can be delivered in conjunction with a blank gelor hydrogel if desired to improve the conduction or distribution of theelectro- thermo- or mechanical signal. By way of example, delivering agel to the target regions within the paravertebral gutter, for example,can allow for expansion of the paravertebral gutter space and subsequentdelivery of a monopolar or bipolar RF catheter after insertion at oneparavertebral level (e.g., endovascularly, transcutaneously) to theregion without disruption of the pleura. The temperature at the targettissue should be 45° C. or more in some embodiments to causeirreversible damage to the neuron. Higher temperatures exceeding 90° C.may cause boiling of the tissue. The generally agreed upon targettemperature for some embodiments is between 60 to 90° C. for about 90seconds. By delivering an anesthetic in the gel, local pain relief canbe achieved prior to the application of RF energy. Subsequently, theenergy delivery can be achieved in a more uniform manner the sympatheticchain. In another embodiment, a ‘blank’ hydrogel is delivered and theproperties of the hydrogel alone temporarily stun or block orpermanently destroy the nerves within the paravertebral gutter. Thehydrogel delivered may be acutely toxic to nerves, such as some of thePluronic formulations, resulting in local cytotoxicity and nerve death.Alternatively, excipients, such as generally recognized as safe (GRAS)excipients may cause changes in ion fluxes in the neurons resulting inneuronal excitotoxic cell death is triggered. By way of example, thedelivery of glutamate to the neurons may trigger local nervedegeneration. In another embodiment, the ‘blank’ hydrogel swellsslightly as it equilibrates with the host tissue resulting in acompressive injury to the nerves within the paravertebral gutter,particularly since they are adherent to the vertebral body or rib. Inanother embodiment, a ‘blank’ gel (e.g., including galvanic alloyparticles) undergoes an exothermic reaction and releases heat as it gelswithin the paravertebral gutter to destroy nerves. In another embodimentthe gel is heated prior to its deposition in the paravertebral gutter,whether at the tip of the catheter delivery system or extracorporeally.In another embodiment it is a cryogel, and is injected in a cooledstate, resulting in temporary or short-term block to the nerve fibers inthe paravertebral gutter. In another embodiment, to overcome thechallenges of advancing a catheter in the paravertebral gutter, an RFcatheter has a port on the front or front sides of the catheter fordelivering an advancing front of gel in front of the RF catheter toprotect the pleura from inadvertent puncture. In this manner a catheterdelivering mechanical or thermal energy can ablate multiple levels ofnerves within the paravertebral gutter.

Drug Delivery Systems and Catheters to Deliver Those Gels.

Control the Spread.

Sympathetic chain neurolysis is performed on a very limited basis,typically in patients suffering from severe intractable pain in latestage cancer in which the benefits in pain reduction out way the risks.Paravertebral or stellate ganglion injections of alcohol or phenol areconsidered risky because of the adverse events that occur in somepatients as a result of their unintended spread (as described, forexample, in U.S. Pat. No. 8,211,017 to Foley et al., which is herebyincorporated by reference in its entirety). Along the sympathetic chainthis can occur at 1) the cervical levels in which the neuromodulatoryagent may spread to the recurrent laryngeal nerve, the vagus, or thebrachial plexus (as is often observed with large volume anestheticstellate ganglion blocks) resulting in adverse events and 2)paravertebral levels (thoracic, lumbar) in which the agent may spread tothe intercostal nerves or through the intervertebral foramen to theepidural space causing temporary or permanent neuritis, neuralgia, andeven rarely paraplegia. Therefore, formulations that can deliver aneurolytic agent into the paravertebral gutter while preventing theuncontrolled spread of the agent to off-target structures, particularlyneural structures including the spinal cord, can be desirable. In oneembodiment, the spread of the neurolytic is limited through theinjection of the neurolytic in a biocompatible drug delivery system,preferably a gel. In this manner, the spread of the drug is determinedinitially to the location of the where the formulation is deposited andultimately resides and subsequently the drug is reaches adjacent tissuethrough diffusion.

Single Level.

Furthermore, the uncontrolled spread of neurolytic agent has limited theuse of a one-level injection therapy to reach multiple dermatomes orlevels. As a result, many clinicians use more than one injection sitesat multiple levels to achieve a continuous paravertebral block. Byloading the neurolytic agent into a gel, the improved control of thespread of the neurolytic agent will also improve the longitudinal spreadwithin the paravertebral gutter.

Local Delivery.

Another objective of delivery of neurolytic agents to the sympatheticchain or nervous system, generally, is to achieve a more consistent,complete and reliable denervation. Recent clinical studies havedemonstrated that more complete denervation of the sympathetic fiberscoursing around the renal artery is linked to improved and moreconsistent outcomes in the treatment of hypertension. By developing amore controlled delivery and more complete ablation, patients may electthe procedure if it has demonstrated to be safe, if the responder rate(efficacy) is high, and the efficacy is consistent. Denervation of thesympathetic chain is currently performed through a minimally invasivesurgical procedure (VATS) on a limited basis for the treatment ofcomplex regional pain syndrome or hyperhidrosis. Several papers havedemonstrated that more complete denervation results in better efficacyin these patients. Sympathectomy (transection and removal of chain), forexample, has superior efficacy and durability than sympathicotomy (inwhich the nerves are cut but the chain is not removed) or clipping ofthe chain. Percutaneous approaches have been limited to single-level RFablation which is widely recognized to result in incomplete chainablation due to the inability to precisely localize the sympatheticchain, resulting in only partial denervation.

There are only a handful of open-label limited patient studies exploringneurolytic ablation (alcohol, phenol) of the sympathetic chain, such asthe stellate ganglia, for the treatment of other indications. In thesecases, the desire to achieve effective denervation of the target tissueis achieved through the injection of large volumes of neurolytic agentin and around the target neural tissue. Presumably, the goal is to bathethe tissue in the neurolytic agent for as long as possible and to ensurecomplete coverage of the target tissue. Again, this high-volumehigh-spread solution comes at the expense of safety, thereby limitingthe applications of neurolytic agents to medically refractory cases.Thus, a localized drug delivery system that delivers the neurolyticagent to the target neurons with minimal disruption to adjacentnon-target neural structures can be desirable. In one embodiment, thiscan be achieved with a formulation in which the drug is delivered withina gel. In this embodiment the boundaries of the gel determine thedeposition of the drug and the subsequent zone of diffusion of the drugout of the gel to the target tissue down the concentration gradient. Inthis embodiment, a smaller volume of neurolytic gel can be delivered tothe patient than is delivered with an injection of a neurolytic alone.

Sustained Release.

In the case of the administration of a neurolytic agent, it is desirablethat the agent be released from the drug delivery system in someembodiments from, for example, 12 hours to four weeks, 1 day to 1 week,or 1 day to 3 days. The drug delivery system, in some cases, affordshigher loading levels of drug with reduced systemic toxicity than can beachieved with the drug alone. High local concentrations of the drug canbe delivered in a sustained way such that although the drug is deliveredabove its therapeutic window, in the local cytotoxic range, the burst orspike in concentration that occurs after the delivery of the drug in abolus can be reduced, and a more typical local sustained release profilecan be achieved. A sustained release therapy for the treatment ofcardiac arrhythmias, particularly ventricular arrhythmias though thedenervation of, e.g., the T1-T4 sympathetic chain can be desirable.

Controlled Release.

In some embodiments, it can be desirable to deliver one, two, or moreagents within its local therapeutic window for a longer period of time,such as with neuromodulatory agents. In one embodiment, these agents aredelivered locally within their therapeutic window, in some cases withouta burst phase in which the agents reach supraphysiologic/toxic levels.Again, with a higher drug loading level than can be achieved with a drugsolution alone, sustained or controlled release of drug can be achieved,for example, for 1 day to 9 months, 1 week to 6 months, or 2 weeks to 4months. In one embodiment, agents that can provide a ‘chemicalsympathectomy’, such as reserpine, can be delivered locally to thecardiopulmonary sympathetic nerves to decrease the release ofepinephrine and other neurotransmitters without destroying thesympathetic nerves themselves. Similarly, the durability of nerve blockwith sympathetic agents can be extended with a controlled releasehydrogel. In one embodiment, the long duration treatment of angina canbe desirable without denervating the nerves. In this manner, reserpinecan be delivered through a controlled release drug delivery system for,e.g., the 3 month to 6 month or more treatment of refractory angina.Patients that undergo a temporary block, may escalate their treatment toa longer-duration temporary block and from there to the permanentneurolytic block if the other blocks are providing adequate relief.

Release Rate.

The release of the drug may be diffusion controlled, chemically orbiodegradably controlled, solubility controlled (of the drug), solventcontrolled (swelling, osmosis, rupture), or externallyactivated/modulated (e.g. magnetic system in which micromovement ofmagnetic beads within a hydrogel causes movement and thus drug release,low frequency ultrasound, electroporation), controlled by the extent ofcrosslinking and crystallinity, the size, thickness or volume of thedrug delivery system, the porosity, and the solubility of the system(e.g. plasticizers or the additional of hydrophilic agents (e.g.glucose, mannitol)) that are rapidly dissolved and create a network orpathway for dissolution of the drug out of the system, or controlled bythe degradation of the hydrogel scaffold. The release rate of the drugmay also be controlled by the pH, ionic strength, temperature, magneticfield, ultrasound, or electrical stimulation. Preferably, the release ofthe agent is not controlled by the degradation of the polymer. Therelease rate may be monomodal, bimodal or polymodal. The release ratemay include a burst phase and then a linear continuous sustained releasephase. The solubility of the drug in the aqueous phase drives the rateof drug release with poorly water soluble drugs providing longer releasethan the higher solubility drugs.

Blank Hydrogel.

Another approach is to deliver a blank hydrogel to the site, defined asa hydrogel without any active pharmaceutical ingredient (API). Thehydrogel may contain a neurotoxic solvent, such as ethanol, DMSO,propylene glycol, glycerine, glycerol, D-Limonene, methanol, ethanol,octanoic acid, 2-octanone, diethyl ether, benzyl alcohol or apreservative such as thimerosal or chlorbutanol. The hydrogel orcrosslinking agents, the pH of the injectate, the pH of the formedhydrogel, the temperature liberated as a result of the gel crosslinking,or the change in the extracellular ion concentrations may cause localneurotoxicity in the absence of an API.

Expanding or Filling the Potential Space.

Given the variability in the position of the sympathetic chain withinthe gutter rostrocaudally, the variable number of rami and visceralfiber bundles coming off of the visceral chain, and the presence ofintermediate ganglia outside of the sympathetic ganglia proper, it canbe desirable to deliver an agent, such as a hydrogel, to fill the entireparavertebral space completely in order to denervate all orsubstantially all of the nerves crossing through the space including thefine hair-width fibers that are not visible to the naked eye. Deliveringthe solution in a suitably viscous formulation, such as a hydrogel,slurry, an injectable foam, a glue or an in situ forming injectablescaffold, including a hydrogel, slurry or other gel that can fill themajority of, or substantially the entire paravertebral gutter. Someexamples of slurries that can be used with embodiments disclosed hereincan be found, for example, in U.S. Pat. No. 7,057,019 to Pathak, whichis hereby incorporated by reference in its entirety. In one embodiment,the therapy is a viscous solution or gel that can be injected with aminimally invasive technique to fill an anatomical space and adheres tothe edges of the tissue. In filling the paravertebral gutter, a morecomplete acute denervation of the nerves in the paravertebral gutter asthe agent is delivered in and around all structures within the gutter.This conformal filling of the paravertebral gutter can be performed witha radiopaque or echogenic polymer.

Preventing Reinnervation.

Approximately 5-10% of surgical sympathectomy patients have laterecurrence of symptoms that is thought to be due to reinnervation.Specifically, they are attributed to incomplete resection or ablation ofsympathetic pathways with 1) remaining residual sympathetic connectionsthat may be strengthened by reinnervation 2) regeneration or survivingneurons and 3) the formation of alternate sympathetic pathways. Morespecifically, the efferent reinnervation is thought to be a result ofpreganglionic sprouting to and new postganglionic sympathetic nerve,possibly in the cervical sympathetic chain. Alternatively, reinnervationmay be a result of afferent nerve sprouting to the cardiac tissue. Oneapproach to preventing regeneration is to deliver a neuroinhibitoryformulation to block regeneration through a lesion site. In oneembodiment, the biodegradable or bioresorbable hydrogel maintains itsintegrity for the duration of attempted regeneration but is completelydegraded or resorbed by the patient's body thereafter. Morespecifically, the bulk of the hydrogel degradation occurs after 2 to 6months, more preferably 2 to 3 months. In this case, the lesion site isthe region that was lesioned by the neurolytic agent, for example, afterneurolysis of the paravertebral gutter between levels T1 to T4, thepresence of a non-growth permissive hydrogel at the site prevents theformation of appropriate connections between remaining sympatheticfibers and thus prevents appropriate reinnervation of the targettissues. Similarly, without supporting glia in the matrix and theprevention of trophic factor diffusion through the gel the absence oftrophic support will provide an additional barrier to axon outgrowth andsubsequent reinnervation. Thus, while neurons initially extend axongrowth cones, an adverse environment will result in dispersion of thesenerve sprouts and ultimately aborted sprouting. At a clinical level,this may translate to fewer late therapy failures as a result ofregeneration and or incomplete denervation resulting in fasterreinnervation.

Porosity.

Controlling the pore size of the gel provides another mechanism tocontrol the release of drugs, particularly low molecular weight drugs,as well as to prevent cellular infiltration or axonal regenerationwithin or across the hydrogel. In some embodiments, the gels can have apore size of less than 50 μm, 20 μm, 10 μm, or even less. These gels canbe non-porous or minimally porous for a period of time (e.g., 2-3months) until the polymer beings to degrade. In some embodiments, thepores are too small for Schwann or immune cell ingrowth (e.g., less than8 μm), and the density of pores is not such that a network is formedbetween the pores. In one embodiment, the use of low MW polymer chainsbetween crosslinks reduces the chain flexibility, reduces mesh size/poresize, and convers an advantage to delay the release of drugs out of thegel. In one embodiment, small pores (<8 μm) assist with the echogenicityof the hydrogel but are smaller than infiltrative cells such as Schwanncells, other supporting cells, immune cells and axons. In still anotherembodiment, the pores are microporous (e.g., from about 100-500Angstroms). Some examples of hydrogels with pores can be found, forexample, in U.S. Pat. No. 8,399,443 to Seward, which is herebyincorporated by reference in its entirety.

The inability of cells to grow into the scaffold can be maintained insome cases for one to 6 months, such as one to two or three months,during which the damaged nerves are attempting to regenerate to targetson the other side of the gel. After this, the degradation of the polymercan result in cellular ingrowth.

In one embodiment, polymers with small pore or mesh sizes act as therate-limiting factor in diffusion of drug out of the hydrogel. Bycontrolling the pore size to less than 5 microns, or more preferablyless than 1 micron, for example, a small molecule may diffuse out of thescaffold but cells such as axons, glia and inflammatory cells cannotenter the scaffold, inhibiting any functional reinnervation. Pore sizecan be varied with the degree of crosslinking and the molecular weightof the crosslinks of the gel.

In another embodiment, the pore size of the hydrogel can be controlledto prevent axon ingrowth with pores less than about 50 microns, 20microns, or 10 microns. Alternatively, the scaffold pores are notinterconnected within the matrix. Alternatively, the pores are notoriented in such a way to promote the extension of cells into thescaffold. For example, scaffolds without pores may not encourage axonalingrowth.

Porous fibrous scaffolds, such as the self-assembling peptide hydrogelmatrix, PuraMatrix, are less desirable in some cases since thepolymerization results in a nanometer scale loose fibrous structure thatis designed to encourage cell infiltration and growth within thescaffold. These scaffolds have been demonstrated to encourage attachmentand outgrowth of neuronal cells, features that would not be suitable forproviding a physical barrier to nerve regeneration. Some self-assemblingpeptide hydrogels are disclosed, for example in U.S. Pat. Nos.8,465,752, 9,011,879, and 9,199,065 as well as U.S. Pub. No.2011/0104061 and 2013/0287698, all of which are incorporated byreference in their entireties. However, in some embodiments, thesehydrogels may not be suitable for this application given the high rateof cellular ingrowth.

Bioadhesive.

The hydrogel can be designed, in some cases, to covalently ornoncovalently, ionically or nonionically, adhere to the adjacent tissueparticularly that of the adjacent paravertebral gutter, including butnot limited to the costotransverse ligaments, the parietal pleura, thevertebral body and/or rib(s), the endothoracic fascia. In oneembodiment, it adheres directly to the nerves that it is surroundingthrough crosslinking with neural tissue. In one embodiment, cationicinteractions improve the adhesion of a hydrogel to the tissue. Assuminggood adhesion to this tissue, there will be very little, if any path forthe regenerating neurons below and above the gel to travel. Systems thatmaintain a stable position and adhere to the site at which they weredelivered for several months and do run the risk of migrating orcompressing adjacent structures such as the lung or spinal cord can bedesirable.

Neuroinhibitory Gels.

The goal of the majority of polymeric scaffolds in development isbiocompatibility, the reduction of further neural damage, the preventionof scar tissue formation and encouragement of regrowth into and throughthe scaffold after an injury by either modifying the scaffold orchanging the agent delivered. In some embodiments, the scaffolds aredesigned to do the opposite: to fill the cavity in order to prevent orinhibit regeneration of nerves across the lesion zone. After nervedamage, surviving axons for growth cones and sprout into the lesion sitein an attempt to reinnervate their target, typically in search ofgrowth-factor mediated guidance cues. This sprouting occurs for a finiteperiod of time before the regenerative attempts are aborted.Alternatively, intact pre-ganglionic neurons may extend axons toinnervate surviving post-ganglionic neurons or, in some cases, afferentneurons. In some embodiments, it can be desirable to inhibit thereinnervation of these neurons through the delivery of a gel alone or agel loaded with neuro-inhibitory drugs, such as inhibitory peptides orextracellular matrix, to physically and/or chemically block theextension of neurites into and preferably around the gel.

In one embodiment, ingrowth into a hydrogel is inhibited by controllingthe charge of the functional groups in the polymer. A neural ornegatively charged polymer typically is non- or less permissive toaxonal ingrowth while a positively charged hydrogel encourages ingrowth,promote tissue infiltration and axon regeneration.

In another embodiment, the hydrogel is designed that it provides astable barrier to neurite outgrowth during the initial phase when axonalsprouting in response to injury is maximal. In this embodiment, thescaffold remains in place within the TPGS for 2 to 3 months.

In another embodiment, the hydrogel can encourage the formation of agrowth inhibitory scar, forming a further communication barrier betweenthe intact upper cervical chain and lower thoracic sympathetic chain.

In another embodiment, the hydrogels can be modified with peptides thatare growth-inhibitory to neurons (as opposed to most modifications toimprove ingrowth).

Location of the Ablation Along Nerve.

Ablation of the sympathetic ganglia and intermediate ganglia result inthe destruction of the post-ganglionic sympathetic cell bodiesinnervating the target organ as opposed to distal ablation andsubsequent rapid regeneration. Similarly, although the afferent andpre-ganglionic nerve cell bodies are not removed, their axons aredestroyed close to their cell bodies in the dorsal root ganglion andsympathetic chain, respectively, resulting in less regenerativepotential than if the axons were destroyed peripherally closer to theirnerve terminal.

Pleural Sealant.

Although the rate of inadvertent pleural puncture or pneumothorax islow, the resulting adverse events, requirement for an indwellingcatheter, and significantly extended length of stay in a hospital makethis one of the top adverse events that clinicians worry about withparavertebral anesthetic blocks. In one embodiment, a hydrogel ortherapy that can act as a tissue or pleural sealant to seal anyinadvertent pleural puncture is desirable.

Echogenicity.

In one embodiment, the hydrogel is naturally echogenic, such that itsinjection and spread is visible under ultrasound guidance. In anotherembodiment, an agent or microbubbles or some either echogenic componentis added to the hydrogel to improve its echogenicity. In someembodiments, the combination of the neuromodulatory agent and thehydrogel improves the echogenicity and/or allows the hydrogel to bevisualized under color Doppler.

Flexibility.

In some embodiments, the gel can be flexible and compliant given itsclose approximation to the lungs and paraspinal muscles.

Swelling.

In some embodiments, the drug delivery systems undergo less than about10%, 5%, or substantially no swelling at all when placed in situ forsafety reasons.

A bioerodible drug delivery system that can control the spread of alow-molecular weight neuromodulatory drug over a period of days ormonths, that has the appropriate rheological and mechanicalcharacteristics to permit the hydrogel spread within the gutter andreduce the off-target spread, provide a non-permissive substrate forneuronal outgrowth and a physical barrier to reinnervation, and/orfunctions as a tissue sealant can be desirable in some embodiments.

In Situ Forming Gels.

Of interest in some cases are in situ crosslinking synthetic polymers.In situ forming materials can be advantageous because they can beinjected through a fine gauge needle as a liquid to the target zone andthen form a solid scaffold in vivo that matches the contours of thepotential space. In situ forming gels may transition from a solution toa gel as a result of pH, temperature, salt, light, biomolecules,solvent-exchange, UV-irradiation, ionic crosslinking, covalentcrosslinking, electromagnetic field. Different types of crosslinking aredescribed in U.S. Pub. No. 2014/0363382 A1 to Campbell et al., which ishereby incorporated by reference in its entirety.

Cross-Linked.

For cross-linked gels, in which two precursor solutions are typicallymixed containing functional groups that react with each other to form acrosslinked gel, by varying the ratio of the precursor solutions, theconcentration of an accelerator or crosslinking agent, the rate at whichthe two solutions form a solid hydrogel can be varied. Upon mixing thetwo precursors (low viscosity solutions approximating that of water),but before the formation of the solidified hydrogel, an ‘intermediate’state of the gel in which the viscosity is between that of the precursorsolution and the solidified hydrogel forms and can be injected into theTPGS and travel to the desired target level, up to 12 levels away,preferably 4-5 levels away, more preferably 2-3 levels or 4 to 15″inches away in some cases.

In another embodiment, one of the precursor solutions (A) is deliveredfirst to fill the target levels followed by the second precursorsolution (B) which crosslinks with precursor A from the distal toproximal target sites. In yet another embodiment, saline is deliveredfirst to clear the TPGS and aid in the creation of the channel prior toadministration of the first and second precursor solutions (A/B). Inanother embodiment, the precursor solution A is delivered first followedby the 50/50% mix of the two precursor solutions (A/B). In oneembodiment, saline is only injected in a small bolus to confirm locationof the needle tip or catheter in the right location but does notpredilate this space.

FIG. 3 illustrates an embodiment of a therapeutic agent delivery systemincluding a catheter 100 that can interface, e.g., removably interfacewith a syringe or other therapeutic agent housing 116 that can include afirst chamber 102 configured to house a first precursor solution 102Aand a second chamber 104 configured to house a second precursor solution104B. The housing 116 can also include a control 106 such as a plungerat its proximal end. The distal end 108 of the plunger 106 when actuatedcan move the solutions 102A, 104B distally through an input port (e.g.,a luer port) of the catheter 100 and downstream into discrete first andsecond lumens 110, 112 within an elongate shaft 111 of the catheter 100.The lumens 110, 112 can in turn merge into static mixer region 114 tocreate a mixed solution, which can be a cross-linked gel in someembodiments as described elsewhere herein. In other embodiments, thechambers 102, 104 can be directly proximate a single lumen whichfacilitates mixing within the lumen. The gel can be delivered to atarget location via a distally or side-facing exit port 146 at thedistal end 118 of the catheter 100. In some embodiments, a curved orbent needle (not shown) can be configured to extend radially outwardlyfrom exit port 146 to assist with targeting depending on the desiredclinical result. In some embodiments, the curved or bent needle canallow the catheter to be positioned endovascularly in a blood vesselproximate the target tissue (e.g., the paravertebral gutter), and thecurved or bent needle can extend through the wall of the blood vesselinto the paravertebral gutter for injection of the therapeutic agent(s).In some embodiments, the delivery catheter 100 can be delivered over aguidewire (not shown), and the delivery catheter 100 can have a proximalguidewire input port, a discrete guidewire lumen, and a guidewire exitport on the distal end, such as a distally-facing exit port. FIG. 4illustrates a distal portion of the catheter 100. FIG. 4A is across-section through line A-A of FIG. 4 (illustrating the elongateshaft 111 and lumens 110, 112); FIG. 4B is a cross-section through lineB-B of FIG. 4 (illustrating the elongate shaft 111 and mixer region114); FIG. 4C is a cross-section through line C-C of FIG. 4.

FIG. 5 is a schematic illustration of a delivery catheter systemincluding one or more therapeutic agent housings (e.g., syringes)removably connected to a catheter 200 configured to deliver a pluralityof therapeutic agents into different anatomical locations, according tosome embodiments of the invention. The catheter 200 can include a firstinput port that interfaces, e.g., removably with a first syringe orother therapeutic agent housing 116 that can include a plurality ofchambers housing precursor solutions for, for example, a cross-linkedgel as described in connection with FIG. 3 above. Actuation of a plunger106 or other control on the proximal end of the first housing 116 willcause the plurality of precursor solutions to flow into first and secondlumens 110, 112 within the first input port and through the elongateshaft 111 of the catheter 200, and distally the first and second lumens110, 112 are in fluid communication with a distal static mixer region114 as previously described. Distal to the mixer region 114 the mixedsolution (e.g., a cross-linked gel) flows distally into a common lumen122, and out a distally or side-facing first exit port 146. The systemcan also include a second therapeutic agent housing 117 that can includeonly a single chamber 150 as shown (or a plurality of chambers in otherembodiments). In some embodiments, the chamber 150 can be configured tohouse a blank protective hydrogel or other therapeutic agent asdescribed herein. Actuation of a plunger or other control 106 will movethe therapeutic agent distally, such as through a second input portwhich can be a luer or other connector, and through a third lumen 129extending distally through the elongate shaft 111 of the catheter 200,and distally past (but separated from and not merging into) the mixerregion 114, and out a distal or side-facing second exit port 148 spacedapart, such as spaced radially apart from the first exit port 146. Thisadvantageously allows for, in some embodiments, a first hydrogel (e.g.,including a neurolytic agent) can be delivered in a first direction(e.g., caudally), while a second hydrogel (e.g., including a protectiveagent) can be delivered in a second direction different from (and insome embodiments opposite) the first direction (e.g., rostrally). Insome embodiments, this can allow for sympathetic neuromodulation (e.g.,denervation) of the thoracic sympathetic ganglia within theparavertebral gutter while protecting the inferior cervical sympatheticganglia within the paravertebral gutter when the catheter is positionedproximate T1/R1. In some embodiments, a plurality of curved or bentneedles (not shown) that can be jointly or independently actuated can beconfigured to extend radially outwardly from exit ports 146, 148 indifferent directions to assist with targeting depending on the desiredclinical result.

In some embodiments, the delivery catheter 200 can be delivered over aguidewire (not shown), and the delivery catheter 200 can have a proximalguidewire input port, a discrete guidewire lumen, and a guidewire exitport on the distal end, such as a distally-facing exit port. FIG. 5A isa relatively more proximal cross-section of the elongate shaft 111 ofthe catheter 200 through line A-A of FIG. 5 (illustrating the elongateshaft 111 and first lumen 110, second lumen 112, and third lumen 129);FIG. 5B is a cross-section more distally, through line B-B of FIG. 5(illustrating the elongate shaft 111, mixer region 114 where first lumen110 and second lumen 112 have merged, and discrete third lumen 129);FIG. 5C is an even more distal cross-section through line C-C of FIG. 5(showing elongate shaft 111 and two lumens therein: lumen 122 (afterjunction of the first lumen 110 and the second lumen 112) and thirdlumen 129.

FIG. 6 is a schematic illustration of a delivery catheter system similarto that illustrated in FIG. 5, except the first therapeutic agenthousing 116 has only a single chamber fluidly connectable via a firstinput port on the catheter 300 to a first lumen 110. The secondtherapeutic agent housing 117 also can have a single chamber fluidablyconnectable via a second input port on the catheter 300 to a secondlumen 129. The first therapeutic agent housing 116 can house a“preformed” hydrogel (e.g., including a neurolytic agent) that does notnecessarily require precursor solutions or mixing immediately prior toinfusion. The second therapeutic agent housing can include a blankhydrogel or protective agent (e.g., hyaluronic acid) as previouslydescribed. FIG. 6A is a cross-sectional view through line A-A of FIG. 6.

Crosslinked PEG.

In one embodiment, a hydrogel such as one from the group of in situpolymerizing poly(ethylene glycol)-based hydrogels is selected for thedelivery of drugs. Crosslinked PEG-based polymers are biocompatible,have controlled crosslinking, degradation, flexibility, and relativelyhigh adhesion strength. In particular the use of multi-arm PEGs, such as4-armed PEG that are functionalized to cross-link with one another canbe of interest. Additional spacers can be added between the 4-armed PEGsto vary the mechanical and drug delivery properties (if desired) of thepolymer. The molecular weights of the PEG arms, on average, may bebetween about 200 Da to 20 kDa, preferably between about 1 kDa and 8kDa, more preferably between about 2 kDa and 5 KDa in some embodiments.The molecular weight of the PEG precursor can be, in some embodiments,between about 4 KDa and 100 kDa, more preferably between about 8 kDa and10 kDa or 20 kDa and 35 kDa. Generally, about 4 to 30% w/w concentrationof precursors are used to prepare gels in some embodiments.

The precursors may be a combination of an ester group on one PEG(precursor A) and a trilysine amine (precursor B). In some embodiments,the precursor A is a 20 kDa N-hydroxysuccinimide end capped PEG which isresuspended at the time of delivery in sodium phosphate buffer, theaccelerator. The precursor B can be, in some cases, a trilysine acetatein a 0.075 M sodium borate decahydrate buffer (pH 10.2). A preservativemay be added, for example butylated hydroxytoluene (BHT). In anotherembodiment, the PEG precursor is a higher molecular weight 31.5 kDaN-hydroxysuccinimide end capped PEG, with the same buffer and trilysineacetate buffer, which together form a gel in about 10 seconds. In thisembodiment, the PEG precursor (lyophilized) is mixed with a diluent(e.g., the trilysine acetate buffer) in a dedicated syringe. Theaccelerator, the sodium phosphate buffer remains in a separate syringe.

These hydrogels remains in the paravertebral gutter for, e.g., between 2to 3 months and then erode through hydrolysis, are resorbed, and fullycleared through renal filtration within, e.g., approximately 4 to 6months. These in situ polymerizing hydrogels have been commerciallydeveloped as an absorbable perirectal spacer (SpaceOAR), and as a duralsealant (DuraSeal, Covidien). In addition to these technologies, othertypes of major hemostats, sealants and adhesives described by Mehdizadehand Yang, Macromol. Biosci. (March 2013) are incorporated by referencein its entirety. By varying the ratio of the precursors, the in situgelation time can be varied. Newer PEG hydrogel formulations have lessswelling, which can be an advantageous characteristic in a formulationdelivered adjacent to the spine.

In one embodiment, a 4 arm PEG amine (—NH2) and a 4 arm PEG NHS esterare mixed in the presence of HCl. The molecular weights and ratios ofthe two PEGs can be varied to control the properties of the polymer. Inone embodiment, after the precursors are mixed, the sol to geltransition can be quick (2-13 seconds) or prolonged (1-2 minutes), toallow the gel time to migrate within the paravertebral gutter beforeremoving the delivery system. In some embodiments, the liquid forms agel in about 2 seconds, 10 seconds, 20 seconds, 120 seconds, or 240seconds. In another embodiment, the crosslinked PEG hydrogels, describedabove, are injected without a neurolytic agent. In another embodiment, aneurolytic agent is loaded into the precursor A phase. In anotherembodiment, a neurolytic agent is loaded into the precursor B phase. Inyet another embodiment, there is one neurolytic agent loaded in theprecursor A phase and another drug loaded in the precursor B phase.

In another embodiment, hyaluronic acid is added to the precursorformulation to increase the viscosity of the solution in order that itcan travel up and down the paravertebral space to the cover the targetthoracic levels, and then gelling after that. For example, the PEG/HAmixture can be delivered between the T2 and T3 ribs (or between R2 andR3) and the agent flows out of the needle/catheter both rostrally andcaudally. The ultrasound probe is advanced rostrally with the flow ofthe agent and when it reaches the lower border of the 1^(st) rib, theflow of material is halted. In another embodiment, when the materialsreach the middle of the border of the 1^(st) rib, the flow of materialis halted. In some cases, when the material reaches the superior or mostrostral border of the first rib, the flow is halted and the caudalspread of the agent is noted prior to removal of the needle. In oneembodiment, HA is crosslinked with bifunctionalizedmaleimide-PEG-maleimide polymer using enzymatic crosslinking and thencrosslinked with a DA click chemistry reaction to have outstanding shapememory and anti-fatigue properties.

In yet another embodiment, the crosslinked PEGs can be mixed with lowmolecular weight PEG, such as PEGs with a molecular weight less than3.35 kDa, including 200 Da, 400 Da, 1 kDa, or 2 kDa linear PEGs. ThesePEGs can assist in modulating the release of drugs from the polymer.

These crosslinked PEGs can be delivered through needles, such as forexample 17G or 18 G needles or with needles as high as 33 G, or about 27G, giving them flexibility in terms of routes of administration(catheter-based or needle-based).

Other technologies that may be adapted for use with systems and methodsas disclosed herein include the Focal Seal product, which forms in situthrough photochemical/chemical polymerization of acrylate-capped PEG-PLLand poly(trimethylene carbonate), or CoSeal, is a covalently crosslinkedPEG product comprised of two 4-arm PEGs with glutaryl-succinimidyl esterand thiol terminal groups.

PEG Generally.

PEG-based hydrogels are biocompatible, have controlled degradation,flexibility, and relatively high adhesion strength, particularly whencrosslinked. Through careful selection of the molecular weight, thenumber of arms, and the reaction conditions, other in situ forming PEGhydrogels can be synthesized. The drug delivery systems may be comprisedof functionalized linear PEG or multi-arm PEG derivatives (with reactivegroups) such as those available from JenKem Technology or Nanocs. Thesefunctionalized systems may be crosslinked with one another through acovalent interaction. PEG may be functionalized with an amine group (orother acid reactive chemical group) that binds to a carboxylic group (orother amine reactive group). These include 3 arm PEG amine (—NH2), 4 armPEG amine (—NH2), 4 arm PEG carboxyl (—COOH), 4 arm PEG SCM (4 arm PEGNHS ester), 4 arm PEG Succinimidyl glutaramide (—SGA) with a longerhalf-life than the —SCM) 4 arm PEG Nitrophenyl carbonate (—NPC) with acarbonate linker between the PEG and NHS ester in which the release ofp-nitrophenol can be traced by UV spectroscopy, 4 arm PEG succinimidylcarbonate (—SC) with a carbonate linker and a longer half-life than—SCM, 4 arm PEG Maleimide (-MAL) which is selective for thiol groups andreacts at pH 5-6.5, 4 arm PEG Acrylate (-ACLT) for use in vinylpolymerization or co-polymerization, 4 arm PEG Thiol (—SH), 4 arm PEGVinylsulfone (—VS) which binds to free thiol groups in aqueous bufferbetween 6.5 and 8.5 pH at room temperature, 4 arm PEG SuccinimidylSuccinate (—SS) with a cleavable ester linker to make it a biodegradablehydrogel, 4 arm PEG Succinimidyl Glutarate (—SG) with a ester linker, 4arm PEG Isocianate, 4 arm PEG Azide, 4 arm PEG norbornene. Similarreactive groups described above can be used with other multi-arm PEGssuch as 6-arm and 8-arm PEGSs. The molecular weight of these polymersmay vary from 1 KDa to 500 KDa. In a preferred embodiment, the polymerincludes 4 arms although PEG-arms may increase to 16 arms. Similarly,any of the aforementioned polymers can be combined to form co-polymers,e.g. PEG-co-alginate, PEG-co-hyaluronic acid, etc. Alternatively,heterobifunctional PEGs, methoxy PEGs (-acrylate, -aldehyde, -amine,-biotin, -carbonate, -carboxyl, -hydrazide, -maleimide, —NHS,-oligopeptide, -phospholipid) can be used, and the like. In addition tothese, Lipid-PEG derivates are also available.

Thermosensitive

In another embodiment, the gel may be an in situthermosetting/thermosensitive gel, which requires a change intemperature to form a physical gel, typically at or below bodytemperature but it can be administered through a single lumen or channelwithout a need for mixing. The concentration of polymer can be such thatit is in a low viscosity state at room temperature (for example, 23-25°C.) and a higher viscosity state at body temperature, or just below bodytemperature at 35° C.

Biodegradable PEG-based copolymers have been fabricated to degradethrough hydrolytic, enzyme-catalyzed or mixed mechanisms. The majorityof these ABA triblock, BAB and AB diblock copolymers are thermosensitivepolymers that gel below body temperature, although some transition fromin the opposite direction (gel at and above body temperature). These arenot covalent bonds but the gel is formed through ionic or nonionicinteractions, such as through chain alignment between theirhydrophobic-hydrophobic regions. By controlling the molecular weight ofthese blocks, the gel transition temperature can occur between, e.g.,25-37° C., more preferably 30-35° C., more preferably 30-33° C. The %w/v of these gels is typically between 5 and 50% concentration,preferably between 5 and 40% concentration, more preferably between 10and 20% concentration. Examples of amphiphilic ABA/BAB triblock and ABdiblock copolymers follow: The hydrophilic A segment in this case is thePEG or PEO and the hydrophobic B segment is most a PPs/polyester/POE/PHBor a PEO penetrating the inner cavity of cyclodextrins. PEG di-block andtri-block copolymers can be formed with polyesters including PEG-PLA,PEG-PGA, PEG-PCL, MPEG-PCL, PEG-PLGA, PEG-LA-PEG, PLGA-PEG-PLGA,PEG-PLGA-PEG, PEG-PCL-PEG, PEG-PGA-PEG, PCL-PEG-PCL or with trimethylenecarbonate (PEG-TMC), PEG-chitosan, PEG-dextrose, PEG-gelatin, and othersuitable combinations of polymers may be selected. In another embodimentpoly(ethylene oxide-co-glycidol)-CHO is formed by mixing aqueous glycolchitosan and poly(EO-co-Gly)-CHO to form a cross-linked hydrogels insitu. Alternatively, an α-cyclodextrin/PEG-b-PCL-dodecanedioicacid-PCL-PEG hydrogel (MPEG-PCL-MPEG) showed promise for cardiacapplications delivering cells and may be suitable for use in theparavertebral gutter. Alternatively, a four-arm PPO-PEO block copolymer(Tetonic) can be modified with acrylates for crosslinking and NHS-groupadded for reaction with tissue amines. PMID 20298770. Alternatively, thePEO-CMC hydrogel (Oxiplex, MediShield, Dynavisc, Aril, FzioMed) has manyof the characteristics to make it an excellent polymer to deliver drugsto the paravertebral gutter. http://www.fziomed.com/core-science/. Stillother polymers include, PEO-PHB-PEO hydrogels. PEG-PCL-PEG orPCL-PEG-PCL (PCEP) which transition from a solution at room temperatureto a gel at body temperature are described. For example, in oneembodiment, a PEG-PCL-PEG hydrogel (2K-2K-2K) forms a thermosensitivehydrogel that can be injected as a solution and forms a gel in situ.Neuroprotective drugs can be safety mixed into the hydrogel solutionprior to injection in situ. Also, pH-block copolymer hydrogels may bewell suited for this application and may include diblock copolymers suchas PEG-PCL, PEG-PLA or triblock copolymers such as PEG-PLGA-PEG.

Pre-Formed PEG Hydrogels.

In another embodiment, PEG can be crosslinked ex vivo, dehydrated andthen crushed. These particles can then be resuspended in an aqueousbuffer with or without drug and stored in a preloaded syringe forinjection. The advantage for this type of delivery system is the abilityto provide clinician with the drug delivery system ready for use. Oneexample of this technology is the TracelT hydrogel (Augmentix), which isan injectable hydrogel that is visible under ultrasound, CT, and MR thatcan be injected with a 25 G needle and remains in place forapproximately three months and gradually degrades through hydrolysis andis bioresorbed over 7 months. The iodinated PEG confers the visibilityunder CT and MR. In one embodiment, a PEG (non-iodinated) slurry isinjected into the paravertebral gutter with a wt % of between 2.5% and20%. The neuromodulatory agents described may be incorporated into thehydrogel. Drugs with low solubility may be incorporated as crystals,particulates, or in a suspension. Higher water solubility drugs,incorporated in a hydrogel, typically only release for hours to days. Ifthey are additionally incorporated into microspheres, liposomes, ornanoparticles, their release rate can be delayed and they can providemore sustained release. Further examples can be found, for example, inU.S. Pub. No. 2014/0363382 to Campbell et al., which is herebyincorporated by reference in its entirety.

Hyaluronic Acid.

The hyaluronic acid (HA) can be formulated with a range of viscositiesand modulus of elasticities. Since it is shear-thinning or thixotropic,it can easily be injected through higher gauge needles and after it isinjected the gel returns to its intramolecular and intramolecular ioniclinks are restored. As the shear force is increased, such as duringinjection, the hydrogel becomes thinner (shear-thinning) allowing thedelivery of some hydrogels through a standard syringe needle or cathetersuch as a 27 G or 29 G thin walled needle or a 30 G needle, asnecessary.

By varying the molecular weight of HA, the degree of crosslinking andthe concentration of reactive HA precursors, hydrogels of varying poresize and viscosity and degradation rate can be produced. HA isnegatively charged and so it can absorb a lot of water and expandforming a loose hydrated network. The HA may be in the form of randomlycrosslinked HA chains and neuromodulatory agents can be encapsulated inthe network without any covalent linkage. HA can be reacted with anexcess of glycidyl methacrylate (GMA) to form crosslinked HAHA can becrosslinked with bisepoxide, divinyl sulfone derivatives under alkalineconditions, glutaraldehyde, biscarbodiimide and hydrazides under acidicconditions.

HA-based hydrogel particles (HGPs) also known as microgels or nanogelscan be synthesized from water in oil emulsion crosslinking to formaqueous droplets of HA. These microscopic gels provide a convenientmethod to deliver drugs in the aqueous phase inside these gels.

Considerable work has gone into developing HA-based gels to solve thevarious needs of dermal fillers based on if tissue plumping or fillingversus small wrinkle filling are needed. As a result, these gels have awide variety of viscosity after injection. The complex viscosity (n*)relates to how the hydrogel flows from the needle and then later howmuch it spreads. Generally, Restylane SubQ>Perlane>Restylane, in thatorder, are more viscous hyaluronic acid fillers than Juvederm,Voluma>Juvederm Ultra Plus>Juvederm Ultra which have low viscosity. Inthese embodiments, it is preferably to have a hyaluronic acid baseddelivery system with a higher viscosity filler so that the agent willremain in place.

The following hyaluronic acid/hyaluronan based products include, forexample, Perlane, Juvederm (Ultra, Ultra XC, Volume XC), Restylane andHyalform, and collagen-based products such as Evolence. Perlane is moreviscous than Restylane containing particles between 750 and 1000microns, similarly Juvederm's line contains hyaluronic acids withdifferent viscosities/thicknesses.

Another advantage to hyaluronic acid based products beyond theirextensive clinical evaluation is that it is possible to dissolve excessfiller with hyaluronidase. In one embodiment, the glycosidic bonds ofhyaluronic acid can be cleaved with Vitrase (ovine hyaluronic acid, 200USP/ml) which can be injected by itself or with saline into the sitecontaining the hyaluronic acid to assist in the diffusion of fluid andclearance of the hyaluronic acid. For example, in one embodiment 20mg/ml of crosslinked hyaluronic acid (cross-linked with BDDE) issuspended in PBS at neutral pH. Lidocaine (0.3%) can also beincorporated the gels to reduce the pain associated with injectionHyaluronidase is also delivered locally to increase nerve permeabilityand is sometimes used in conjunction with 10% hypertonic saline as aneurolytic agent and to break up adhesions in the spine (1500 U/10 ml).Conventional hyaluronic acid hydrogel crosslinking can be employed, asdisclosed, for example, in U.S. Pat. No. 4,582,865 to Balazs et al.,which is hereby incorporated by reference in its entirety.

Ethanol Based Systems.

With hydrophobic drugs and hydrogel monomers or hydrogels are soluble inethanol, a high drug-loaded hydrogel can be created. Since ethanol canact as either a solvent for the polymer as well as a neurolytic agentand the alcohol is rapidly absorbed once placed in the body, novelhydrogels using alcohol may be possible. In one embodiment theneurolytic agent is coadministered with the hydrogel in anaqueous/ethanol solution. The ethanol, between, for example, 10 and 50wt %, more preferably 30%, can be incorporated in a HA- or PEG-basedhydrogel. With regard to the in situ forming crosslinked hydrogels, theethanol can either be incorporated in the precursor solution prior tomixing the agents and formation of the gel. This may be reflected in thekit in which the alcohol is an additional vial.

In another embodiment, the active agent is added to the polymer solutionwhere it is either dissolved (soluble) or dispersed(insoluble—suspension/dispersion) in the polymer solution. After thesolution is injected into the target site, the solvent (ethanol)diffuses away from the polymer-drug mixture while water diffuses in,causing the polymer to turn into a solid drug delivery implant. The drugis subsequently released by diffusion or dissolution. In one embodimentthe drug is dissolved in ethanol and the monomers PEG methyl ether(MPEG)-PLA, acrylol chloride macromonomer, itraconic acid, and MPEGmethacrylate to form poly(LA-IA-MEG). In one embodiment, ethanol isadded to the aqueous phase of the polymer and modifies the gelationtime. Addition of ethanol, for example 25% ethanol, improves themechanical properties of the gel.

Poloxamers.

The Pluronic class of polymers are nonionic triblock copolymers ofpoly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)(PEO-PPO-PEO) that are thermoreversible polymers that are thought toform as micelles aggregate together above the critical micellularconcentration (CMC) to form a gel. Poloxamers form hydrogels ashomopolymers or as uncomplexed multi-block copolymers. Poloxamerproperties can further be controlled through crosslinking to improve therelease of drug and modify the sol-gel transition behavior and criticalgelation temperature and concentration. Poloxamers, such as P407, can beinjected into the potential space and used to protect tissuesencapsulated in the semi-solid gel from thermal damage such as RF,ultrasound, and radiation. Poloxamers form at between 10 and 60%wt/volume, more preferably between 20 and 50%, more preferably 25-35%wt/vol. The P407 is thermoreversible (15.4% in water) and transitions toa semi-solid at body temperature. Pluronic F-127 is a nonionicsurfactant polyol (MW 12.5 KDa) with 7% PPO that at low concentrationsforms micelles and at high concentrations packs to form high modulusgels. HPMC can be added to Poloxamers to prolong the gelation time. Inanother example, a polaxamer-heparin hydrogel if formed from poloxamer(PEG-propylene glycol-PEG). In another example, 20% ethanol is added tothe Poloxamer solution without affecting the concentration for gelation.At 30% ethanol and 35 wt % F-127 can form at 20 degrees Celsius. Asanother example, two Pluronic block copolymers can be mixed to vary theproperties of the gel. In one embodiment, Pluronic F127 can be loadedwith the neurolytic agent and then F-127 can be mixed with F-68 toassist in reducing the gelation temperature.

Other Polymers.

The aforementioned not limiting, there is an unmet need for aninjectable gel, that includes a glue, slurry, scaffold, or hydrogel- ora more simple emulsion or other viscous solution formulation that candeliver a neuromodulatory agent or combination of neuromodulatoryagents. In some embodiments, the therapy can include neuromodulatoryagent(s) delivered in a gel. In some embodiments the neuromodulatoryagent is co-delivered with an anesthetic and/or contrast agent. In someembodiments, the anesthetic, if delivered, is administered immediatelyprior to the injection of the therapy.

Formulations include gels, and more particularly hydrogels that can formeither through physical crosslinking (ionic interactions, hydrogenbonding, hydrophobic-hydrophobic interactions) or chemical crosslinking(Schiff base crosslinking, Diels-Alder crosslinking, Michael addition,CuAAC, SPAAC, Thiol-ene, Oxime, and Radical polymerization. Thepolymerization of hydrogels can be induced by physical mixing,temperature, pH, UV light exposure, and/or ionic concentration.Polymeric gels may be homopolymers, copolymers, or multi-polymerinterpenetrating polymeric hydrogels. The gels may be nonionic(neutral), anionic, cationic, amphoteric electrolytes (ampholytic, acidand base groups), or zwitterionic (anionic and cationic groups in eachstructural repeating unit).

Echogenicity

In some embodiments, the gel can be sufficiently echogenic to allow theclinician administering the therapy to confirm its appropriate deliverywithin the paravertebral space as well as to track its subsequent spreadup and down the paravertebral gutter. In some embodiments, the gel haslow to no internal pores, decreasing the rate water permeation throughthe gel, decreasing the rate of drug release, and preventing theingrowth of neuronal and non-neuronal cells.

After the gel has formed at the site or has been delivered to the site,the gel may provide for sustained or controlled release of the agent.This can provide more effective means to deliver therapeutic orneurotoxic concentrations locally to the target tissue. In the case of aneurolytic agent, this can allow more complete denervation of the nervesthat are in direct contact with the gel whether through 1) encapsulatedor surrounded with the gel, 2) partially surrounded by the gel on oneside and another anatomical structure on another side (blood vessel,bone, organ, adipose, fascia, extracellular matrix, lymph node etc.), orindirectly via drug diffusion across extravascular tissues or adiposetissues. By completely filling the potential space, the thread-like ramicommunicantes that are not visible to the naked eye are also destroyed.This can be advantageous since if they are not transected or cauterizedduring a surgical sympathectomy or RF percutaneous sympathectomyprocedure, they provide a surviving pathway or, alternatively, a pathwayfor appropriate regeneration or reinnervation of fibers later.

Blank Gel.

In another embodiment, blank (non-drug loaded hydrogel) can be injectedto off-target neural structures to act as a buffer to prevent drugspread to neural or other tissue that needs to be protected from theeffect of the neuromodulatory agent. Subsequently, a drug-loadedhydrogel can be delivered to the desired levels for ablation. The blankhydrogel can be injected up against with the other neuromodulatory-gel.In the case of short-acting agents, the blank gel only needs to protectadjacent neural tissue as long as the neurolytic agent is released andso the gel in some cases preferably degrades faster in the tissue thanthe neurolytic-loaded hydrogel. In a further embodiment, the blank andneurolytic-loaded.

Polymers.

The drug delivery system may be comprised of a nondegradable polymersuch as silicone, cellulose or ethylene vinyl acetate copolymer (EVAc),polystyrene, acrylamide, or cyanoacrylate glues. However, in someembodiments, the drug delivery system is comprised of biodegradable orbioerodible polymers. The drug delivery systems may be comprised ofnatural polymers including, but not limited to glycosaminoglycans andpolysaccharides including but not limited to collagen, alginate,chitosan, pullulan, hyaluronic acid, hyaluronan, gelatin,carboxymethylcellulose (CMC) silk fibroin, dermatan sulfate, chitin, andchondroitin sulfate and derivatives thereof. Synthetic biodegradablepolymers such as polylactic acid (D-, L-, D/L, PLA), polyglycolic acid(PGA), polylactic-co-glycolic acid (PLGA), polyaminoacids,polyorthoesters (POE), polycaprolactone (PCL), polyphosphoesters (PPE),poly(urethanes), polyanhydrides, polyimide, propylene glycol,poly(ethylene oxide), olyethylene glycol (PEG), poly(2-hydroxyethylmethacrylate) (PHEMA), and poly N-(2-hydroxypropyl)-methacrylamide(PHPMA), poly(methylmethacrylate) (PMMA) (Artecoll orArtefill—microspheres in a collagen gel), polyacrylamide (Aquamid)poly(ester urethane), cyclodextrin, poly(alkene oxide), poly(hydroxyalkanoate), poly(R-3-hydroxybutyrate) (PHB) andco-hetero-polymers thereof. Other components include glycerol,poly(glycerol-co-sebacic acid), and poly(ethylene oxide) (PEO) Thesepolymers can be further modified to create hydrogels with cholesterolmethacrylate or 2-ethoxyethyl methacrylate (EOEMA). The polymers caninclude linear backbones or star or branched polymers with molecularweights ranging from 1 kDa to 500 kDa, more preferably 2 kDa to 300 kDa.Some examples include but are not limited topoly(epsilon-caprolactone-co-ethyl ethylene phosphate, a copolymer ofcaprolactone and ethyl ethylene phosphate (PCLEEP), polilactofate-PLA(PPE-PLA) copolymer (Paclimer Microspheres), polyanhydride-co-imide,poly(TMA-Tyr-:SA:CPP 20:50:30) polymer (Chiba et al), poly(vinylalcohol) based cryogels. For these purposes, polyscaccharides,N-isopropylacrylamide (NIPAAm) copolymers (thermosensi), poloxamer andits copolymers, pEO-P(D,L)LGA copolymers and liposome based systems. Inone embodiment, copolymerization of NIPAAm, acrylic acid andhydroxymethacrylate and TMC (HEMAPTMC) may be suitable for injection.

Additional biodegradable polymers, solvents, aqueous carriers, aredescribed in, for example, U.S. Pat. No. 6,545,067 to Buchner et al. andU.S. Pub. No. 2014/0363498 to Sawhney et al., both of which areincorporated by reference in their entireties).

Natural Gels Based Gels:

Chitosan-β-glycerophosphate/hydroxyl-ethyl cellulose (chitosan/β-GP/HEC)hydrogels, chitosan-polylysine hydrogels, alginate hydrogels, andcollagen hydrogels can also be utilized in some embodiments, as canrapid gelling hydrogels composed of mixtures of chitosan-thiol modifiedand polylysine-maleimide give gelation times of between, e.g., about 15and 215 seconds. These hydrogels have excellent hemostatic properties.In another embodiment gelatin methacrylate can be utilized.

Fibrin-Based Gels.

Chondroitin sulfate proteoglycan gel (CSPGs), such as Aggregan,Neurocan, Brevican, Versican, and NG2 exert inhibitor influences on axongrowth as can urinary bladder matrix (UBM). Fibrin and fibrinogen,whether mammalian or non-mammalian, may be used as an injectable gel butmay be less desirable because of its ability to support neuriteextension. Matrigel and other fibrin gels in some cases do not stayaround for long enough to prevent regeneration. However, fibrin may beconjugated with PEG to improve its characteristics. In one embodiment,the drug is delivered in a crosslinked fibrin matrix, sealant glue orslurry, such as the FDA approved Tisseel. By varying the concentrationof thrombin used to induce polymerization, the solution to geltransition can be controlled.

Other commercial formulations that may be suitable include collagenbased gels such as Evolence (with Glymatrix technology), calciumhydroxyapatite microspheres (CaHA, Radiesse), and pro-fibrotic PLLAmicrospheres (Sculptra), and/or the fibrin matrix or glue (Tisseel) madeof fibrin and thrombin.

Biodegradable alginate or collagen, or agarose-chitosan hydrogels. Inone example a chitosan hydrogel is prepared by mixing chitosan (2% w/v)with dibasic sodium phosphate (DSP) to for a gel that at bodytemperature. In one embodiment, the BST-Gel platform (Biosyntech,Canada) is utilized, that includes chitosan neutralized withbeta-glycerophosphate (GP) which forms a gel at room temperature.

Pullulan.

In another embodiment hydrogels made from pullulan, a naturalpolysaccharide, that have excellent oxygen barrier properties, highlytransparent, and is non-hydroscopic, may be used. Acutely, the polymermay result in pH changes in situ that may be toxic to neurons. In oneembodiment pullulan is modified to form pullulan methacrylate (PulMA) tohydrogels to deliver drugs.

Thermochemical Ablation.

The use of liquid alkali may be a safe and effective method to ablatenerves. Permeable oil-packed alkali metal sodium-potassium (Na—K), inwhich the oil controls the rate of heat release during the Na—K reactionwith water in living tissue. Alternatively, the delivery of a singleelectrophilic reagent, such as acetyl chloride (AcCl, 4 mol/L) or aceticanhydride (Ac(2)O) can be delivered in vivo to cause a significant pHchange or temperature increase of around 30° C. (PMID 23311380). Twocomponent systems containing HCl or acetic acid in either NH₄OH or NaOHalso have potential. Similarly, the exothermic reaction caused by theinitiators and the hydrogel polymerization in situ can liberate heat andcause nerve degeneration.

Delivery of Cells for Applications where Neuroregeneration, NeuronalSurvival, or Neuroprotection are Desired.

In another embodiment, pluripotent cells can be delivered in thehydrogels to differentiate into neurons, glia, or other supporting cellswithin the sympathetic chain. These transplanted cells can provide forthe release of growth factors, cytokines and anti-inhibitory moleculesto promote regrowth, to target the sympathetic afferent and efferentnerves. In one embodiment, these cells secrete nerve growth factor(NGF).

Retrograde.

In some embodiments, the drugs can be delivered to the ganglia afterinjection into the pericardial sac or into the heart. In theseembodiments, the drug can be delivered transcutaneously into thepericardial sac or other target heart location. The drugs are taken upat the nerve synapse and are retrogradely transported back to thesympathetic efferent ganglia located in the sympathetic chain or theafferent visceral nerves located in the dorsal root ganglion. In anotherembodiment, drugs are delivered locally within the pericardial sac totarget the interneurons located in the ganglionated plexi located aroundthe heart.

Anterograde.

In other embodiments, it can be desirable to deliver the drug from thesympathetic chain to the afferent and efferent nerve terminals/synapsesin the heart. In this manner, drugs that will be taken up at the soma ordendrites and delivered after anterograde transport to the heart and/orlungs.

Circumferential.

One of the challenges with injecting neurolytic agent around a vessel isachieving circumferential delivery of the drug. In one embodiment, apre-configured fiber is injected transvascularly out of a curved needleand the polymer self-forms a coil-like shape around the vessel thatprovides sustained release of a neurolytic agent circumferentiallyaround the vessel. The noodle may have a curved shape within the lumenof the needle or it may assume a curved shape as it exits the lumen ofthe needle and comes in contact with water.

Mechanism of Drug Release.

In applications requiring the sustained release of a neurolytic agentfor days to weeks but the prolonged presence of a drug delivery systemsuch as a hydrogel to prevent nerve regeneration, the release of thedrug is in some embodiments not controlled by the degradation of thepolymer. Sustained release gels may additionally incorporate complexes,microspheres, nanospheres, nanocrystals, micelles, liposomes,nanoliposomes, or nanocomplexes, as known in the art. Alternatively, aviscous formulation such as a suspension, emulsion or a slurry can bedelivered to the tissue, such as a slurry of hydrogel particles, inwhich the release rate is primarily controlled by the environment intowhich it is injected. Drug diffusion through gels can also be controlledby the polymer concentration, the degree of swelling (hydration factor).

Microspheres.

In order to provide more controlled release and reduce the burst, thedrugs may be loaded into microspheres. These microspheres can bedelivered in a slurry or incorporated into a hydrogel. In oneembodiment, the microspheres are incorporated into an in situ forminghydrogel. In another embodiment they are incorporated into a lyophilizedphase of the in situ polymerizing hydrogel in which they will only getresuspended when they are ready for use. The microspheres may releasethe neuromodulatory agent with or without neuromodulatory agent alsoloaded in the hydrogel phase. Alternatively, the microspheres mayrelease one agent and the aqueous phase of the hydrogel may release adifferent agent. In this embodiment, the release rates of the drug fromthe microsphere and gel phase may differ. Typically the release of drugfrom the microspheres will be slower than that from the hydrogel. Insome embodiments, the microspheres are biodegradable so that they areeventually cleared from the site of injection.

Microspheres can be formed by single or double-emulsion. In oneembodiment, a poly(ethylene glycol) based microsphere system if formedwith a water-in-water emulsion process. A single (W/O) or double W/O/Wemulsion process can be used to prepare the drug. By adjusting thenumber of sites of hydrolysis, emulsion conditions and varying the PEGmolecular weight the degradation and erosion can be controlled. In oneembodiment, PEG-diacrylate (PEGDA) chains are reacted with dithiolmolecules to form hydrolytically labile ester linkages proximal tothioether bonds, PEG-dithiol (PEG-DTT). A water-in-water emulsionprocess is then used to synthesize the PEG microspheres. Alternatively,the PEG-DTT polymer solution can be dispersed in a 40 kDa dextran-richaqueous phase and the acrylate groups in the droplets can be crosslinkedwith UV light to form microspheres. The microspheres are removed fromthe emulsion by dilution of the dextran-rich phase and centrifugation.

Nanoparticles

If intracellular delivery of these agents is desired, theneuromodulatory agent can be encapsulated within nanoparticles which aremore readily endocytosed into the cells. Alternatively, the goldnanoparticles can be conjugated directly to the neuromodulatory agentsas these readily accumulate within neurons.

Nanocrystals.

For example, a drug may be formulated in nanocrystals and dispersed in adrug delivery system. The crystals can be sieved to achieve a particularrange of particle size in order to better control the release of drug.Alternatively, the drug may be micronized to reduce the size of the drugparticles.

In some embodiments, the drug release occurs through diffusion of thedrug from the drug delivery system. In one embodiment, the drug crystalsare loaded into the hydrogel, and the release of the drug occurs as thehydrogel absorbs water after implantation causing solubilization of thehydrophobic drug crystal and subsequent sustained diffusion into thesurrounding tissues, thus the polymer hydrogel itself is imparting

Coprecipitates.

Instead of microspheres, the poorly water soluble drugs may be complexedwith one or more pharmacological carriers. In one embodiment an inertwater-soluble carbohydrate is selected to form a coprecipitate with aneuromodulatory agent in order to better control the release profile ofthe drug. For example, the drug can be coprecipitated with fructose,polydextrose or xylose at a ratio of drug:carrier of between 1:5 to1:20.

Embedded drug delivery systems to facilitate controlled release of drugsfrom the hydrogels include The drug is loaded into microspheres in ahydrogel that provide the rate-limiting release of the drug. Thepolymers may degrade by bulk or surface erosion over a period of days toweeks to months, as needed for a given application. For example, in oneembodiment, a thermoresponsive Poloxamer gel is combined with pHsensitive chitosan nanocomplexes containing the active agent.

Polymer Conjugation.

The polymer may be conjugated to the drug with an enzymatic orhydrolytic linkage. In one embodiment, the linkage is a hydrolyticlinkage off of the backbone of is the polymer and upon delivery into anaqueous environment, hydrolysis causes release of the drug.

Lipophilic for Depots.

Highly lipophilic agents may be particularly desirable agents to deliverto nerves and are efficient in forming depots in the fascia and adiposetissue through which these nerves run.

Differential Sensitivity.

In another embodiment, a chemical agent is delivered that ispreferentially more sensitive to one type of neural fiber than another.For example, sympathetic efferent fibers are recognized to be moresensitive to anesthetic than sensory afferent fibers. In anotherembodiment, the soma themselves are targeted such as the sympatheticganglia or the dorsal root ganglia.

A further embodiment includes adding proteolytically degradable sites inthe PEG system, enabling both proteolytic and hydrolytic or mixed-modedegradation.

Free Base.

Alternatively, the drug can be converted to its free base, whereapplicable, and injected or delivered as a viscous paste directly orincorporated within a drug delivery system.

Drug Loading Levels.

The drug loading level can be in some embodiments about 1% to 80%, about5 to 50%, or about 5 to 20% in some cases

Volumes of Agent or Formulation Administered.

Although the physician will have the discretion to deliver theappropriate volume of therapy to the paravertebral gutter, the followingtable provides a guide to volumes injected according to someembodiments. More typically volumes from about 1 ml to 30 ml aredelivered in and around various neural targets. In the paravertebralgutter, volumes between about 1 ml and 20 ml are delivered to treat thetarget vessels or organs, more typically between about 2.5 and 10 ml, or1 and 5 ml.

Specific Dermatomes.

In some embodiments, the agent would be delivered to the T2 to T5dermatomes, or the T2 to T4 dermatome. In some instances patients willrespond better if the T1 to T5 levels are treated or only the T1 to T3dermatome. Similarly, some patients with a fused inferior cervical andT1 ganglion, the stellate ganglion may benefit from therapy beingdelivered to this level as well.

TABLE 2 Spread of chemical agent Volume Distance Spread Failure 2-5 mlSingle level None or minimal — 5-8 ml Three level None or minimal — 10ml 3.5 ± 1.5 dermatome 70% paravertebral, 10% cloud 6% segmentsdistribution, 7% intercostal 15 to 20 ml Avg. 5 levels somaticUnilateral (occasionally bilateral), 6-10% (range 1-9), Avg. 8 levelsparavertebral, intercostal, epidural sympathetic (range 6 to 10)dermatomes

Gel Set Times.

In situ crosslinkable agents can be formed in which both reagents,typically with at least one of them a polymer, are modified with afunctional group to allow crosslinking. By varying the concentration ofthe agents, the degree of substitution of the active/functional groups,and the molar ratio of the two crosslinking agents, the gelation can bemodulated. In gels that have a sol-gel transition, this can occur frombetween 1 second to 5 minutes, in some cases between 1 to 3 minutes.This may refer to the time after initiation (e.g. temperature change, pHchange, crosslinker mixing) until the formulation is no longerinjectable or flowable, even if it hasn't yet reached it maximalstrength characteristics.

Minimal or Non-Swelling.

In some embodiments, the formulation should not result in a clinicallysignificant change in size, such that upon delivery there is less than50%, preferably less than 30% or more preferably less than 10% swelling.The swelling may be cationic or anionic or, in the case of cross-linkedhydrogels it may be a function of cross-link density.

Durability of Effect.

Agents may be delivered that cause short-term denervation followed byaxonal sprouting and regeneration. Agents may be delivered that resultin long-term permanent denervation either by destroying fibers that arenot capable of regeneration, by destroying a long enough region of theaxon or axon bundle that the fibers cannot regenerate or lack theappropriate trophic factor support to guide the fiber regeneration backto the original source, or by destroying the soma themselves. Agents maybe delivered that provide for an inhibitory environment to prevent axonregeneration.

Other Target Tissues.

In another embodiment, the injectable formulation can be deliveredlocally until it covers the desired target neural tissue even in anunbounded space, such as the case with the celiac plexus or otherperivascular plexi, in and around the aorta and aortic arch, in andaround the azygous, hemiazygous, accessory hemiazygous vein, or from thebronchial arteries to the region containing the plexi in and around thelung hilum. In yet other embodiments, the viscous solution or hydrogelcan be injected perivascularly to obtain substantially 100%circumferential delivery of the neuromodulatory agent.

Degradation or Erosion and/or Resorption.

The degradation, erosion, absorption or clearance of these drug deliverysystems can be in some embodiments between one week and one year,preferably one week and 6 months, more preferably between one and threeweeks in the blank hydrogel embodiments, and between one week and 9months in the neurolytic-hydrogel group, preferably between 2 to 6months. If the system undergoes enzymatic or hydrolytic degradation,this begins after the nerves have become chronically degraded, e.g.,between two or three months. The scaffold or hydrogel can be designed tofully resorb within the body after the period for axon sprouting andattempts at reinnervation/regeneration is over. Typically this will beon the order of 2 weeks to 1 year, more preferably 2 weeks to 6 months,more preferably two to four months. The hydrogel may be biodegradable orbioerodible and can be ultimately cleared from the site.

Timing of the Delivery of the Formulation.

In one embodiment, the therapy is delivered in as a one-time inpatientor outpatient procedure. However, repeat procedures may be necessary ifthere is some reoccurrence of symptoms. In the preferred embodiment thehydrogels degrade within two to three months after injection and there-establishment of connections is prevented. Thereafter the hydrogelmay be gone should an additional procedure be required.

Frequency of Administration.

Current chemical neurolysis approaches may not be as long lasting asenergy-based approaches such as radio- or cryofrequency for achievingnerve degeneration. As a result, chemical denervation approaches such asphenol or alcohol may in some embodiments require a second or thirdapplication/procedure in order to maximize effectiveness. Effectivenessmay be maximized by either extending the lesion, treating more fibers,or preventing regeneration. In one paper 19/23 patients required oneinjection of alcohol in the lumbar chain only and the remaining 4required a second block.

In another embodiment, the neurolytic agent is administered first andthen one or two weeks later, the biodegradable hydrogel is inserted.

Example 1

Sustained release. HA was conjugated to 4-arm PEG-amine (10 kDa) with1-ethyl-3-(3-dimethlaminopropyl)-carbodiimide hydrochloride as a crosslinker at a 100:1 ratio. Reserpine crystals were then incorporated intothe HA/PEG hydrogel at a loading level of 150 μg in 10 ml hydrogel. Wheninjected into the subcutaneous space, the reserpine was released at 15%within the first 1 hour, 50% within 6 hours, 80% at 18 hours and 100% at24 hours.

Example 2

In another embodiment, NETS-ester activated chondroitin sulfate iscrosslinked with 6-arm PEG amine. After an initial burst of 15% of thedrug loading, the reserpine is mixed in to release approximately 20-50μg per day from the hydrogel for 3 to 4 weeks.

Example 3

In one embodiment, NGF is delivered from an in situ formingthermosensitive hydrogel, such as PEG-PCL-PEG or heparin-poloxamer (HP)gel such as those used for delivering NGF to the spinal cord to treatspinal cord injury in rats (PMID 26472614). Additional hydrophilic andhydrophobic polymeric additives, such as PVA, PEG or PCL can be added tovary gel concentration or drug release. In another embodiment, NGF isreleased from a crosslinked 20 kDa 4-arm PEG homopolymer. The largersize of the molecular delivered permits the sustained release of NGFwithout any additional additives.

Example 4

In another embodiment, NGF is delivered in a diblock copolypeptidehydrogel (DCH) to serve as a depot for drug release at a drug deliveryrate in steady state at about 20 ng/ml.

Example 5

In one embodiment solutions of covalently crosslinked multi-armed PEGhydrogel particles of about 70 μm in diameter are formulated in a PEG(20 kDa) water solution to improve the injectability of the slurry.

Example 6

Valproate-loaded chitosan nanoparticles were prepared. The chitosansolution (0.3% (w/v) in 5.54% sodium acetate, pH 5.5) was added dropwiseto the continuously stirring mixture of tripolyphosphate (TPP, 2.5% w/v)and sodium valproate (25 mg/ml). The slightly negatively chargedchitosan nanoparticles form through ionotrophic gelation with particlesizes less than 100 nm a loading level of up to 50% and drug release forabout a week. The nanoparticles are loaded in a PEG-PLGA-PEG triblock(33 wt % solution, MW 3300) hydrogel, resulting in valproate drugrelease for a week and persistence of the hydrogel in vivo for over amonth.

Example 7

A Poly(N-isopropylacrylamide) (pNIPAm) based thermosensitive microgelwas loaded with desipramine (50 mg/ml) hydrochloride, a cationic drug,which binds to the polymer via the carboxyl groups. The resultantthermoresponsive polymer microgels range in size from 500 to 800 μm inwater. Drug was released from the hydrogel for between 1 and 3 days.

Nanocrystals.

In one embodiment, an in situ thermo-sensitive hydrogel loaded withnanocrystals (NCs) of a hydrophobic drug such as reserpine at a drugloading of up to 5 mg/ml, more preferably 3 mg/ml. In anotherembodiment, the gel is loaded with paclitaxel at up to 3 mg/ml. PMID24512789. In another embodiment, a PTX-NCs-Gel system with PluronicF-127 uses PTX-NCs and Taxol as controls.

Drugs

Overall concept of drug delivery. In some embodiments, chemical agentsmay be delivered to or near the neural target tissue in order to affectpulmonary function. Chemical ablation may be desirable over thermalablation approaches in some cases because it may reduce or eliminatespain and unpleasant sensations during the procedure. The agents may bedelivered by a percutaneous, transcutaneous, or endovascular approach oreven through an endoscopic or thorascopic approach. The agents mayresult in chemoablation or chemolysis or chemical sympathicolysis insome cases. The delivery of the therapeutic composition or agent can becontrollable with respect to the number of levels above and below theinjection site and the neural targets within the paravertebral space.The agent delivered can in some embodiments travel both medially to theparavertebral space and rostrally/caudally through the subpleural spaceto cover three or four dermatomes.

Generally, chemical agents that exert a specific neuromodulatory effecton neurons can be desired depending on the desired clinical result. Mostof the agents developed to impair or destroy the sympathetic nervoussystem are targeted at post-ganglionic neurons. However, some approachesto the destruction of the pre-ganglionic neurons or transmission betweenpre and post ganglionic neurons can also be utilized. Classes of drugsinclude but are not limited to ionotropic, chronotropic, metabotropicdrugs that suppress neurotransmission, anti-depressants,anti-psychotics, NMDA antagonists, opioid analgesics, anti-depressants,alpha-1 or beta2-adrenergic antagonists or alpha-2 agonists,calcium-channel blockers (CCBs), anesthetics, neurotoxins, neuroablativeagents, depolarizing agents, non-depolarizing agents, hyperpolarizingagents, sympathicomimetics, sympatholytics, sympathetic antagonist,sympathotoxins, immunosympathectomy agents, auto-immune sympathectomyagents, anti-neuronal immunotoxin agents, antihypertensive agents, TRPV1antagonists or agonists, tricyclic anti-depressants, low and highaffinity Na+ blockers, imidazoline receptor agonist, ganglionic blockingagents, neurotransmitters, parasympathicomimetics, corticosteroids, andanti-neoplastic drugs. These agents may be delivered alone or incombination to exert a neuromodulatory effect directly or indirectly.These agents may result in a temporary block, a long-term-block, atemporary degenerative response without cell recovery, or a permanentdegenerative effect. These methods may result in reversible orirreversible effects. These agents may also have an anti-inflammatory orneuroprotective effect. In some embodiments, it can be preferable toco-deliver anesthetic with or without epinephrine or norepinephrine inthe neuromodulatory solution in the paravertebral space to reducecomplications.

Objectives/Unmet Need with Drugs.

Cardiac disease, and in particular heart failure, is characterized byincreased sympathetic release of norepinephrine (norE), depleted cardiacstores of NE, accompanied with a defect of norE uptake in the cardiacsympathetic nerve terminals. The defect in the uptake is in part due toa reduction in noreE transporter density in the sympathetic nerveendings and may be a major contributor to the elevated myocardialinterstitial norE. Increased interstitial norepinephrine reducesmyocardial adrenoreceptor density, increases myocyte apoptosis, andlowers the threshold for cardiac arrhythmias. In addition, these acutesurges or norE are thought to increase the propensity for myocardialinfarction in patients with coronary artery disease as the resultantblood pressure surge and vasoconstriction trigger a fissure in acoronary artery plaque, providing a thrombogenic focus together withincreased

Given the high levels of norepinephrine release that occur when thesympathetic ganglia are surgically transected, thermally ablated, ordenervated with an excitatory neuromodulatory agent or agents thattemporarily increase the levels of norepinephrine at the synaptic cleft,the development of neuromodulatory agents that directly or indirectlyblock or reduce the release of norepinephrine acutely, subacutely, orchronically are desirable for certain indications, particularly cardiacindications. The therapy, including a neuromodulatory agent and acarrier, can be delivered to the paravertebral gutter, containing thesympathetic chain, intermediate ganglia, rami communicantes andintercostal vessels. The carrier can be, for example, a hydrogel orother viscous formulation that can be used to deliver theneuromodulatory agent. The therapy may also be delivered tointermediate/accessory ganglia lying along the nerve roots or ramicommunicantes or along the nerves as they course to the visceral organsand vessels. Alternatively, the therapy may be delivered specifically tothe region in between or surrounding the dorsal root and the dorsal rootganglion (DRG), particularly if sympathetic fibers have been identifiedinnervating the DRG. In particular, the selection of neuromodulatory orneurolytic agents that directly or indirectly reduce the release ofnorepinephrine from sympathetic nerves followed by or in concert withtriggering neuronal cell death such as through necrosis, autophagy orapoptosis, “dark” compacted death or a combination of these, can bedesired.

In one embodiment, it can be desirable to deliver a neurolytic agentthat can be taken up locally at the sympathetic ganglia (pre- orpara-vertebral, may be mixed with parasympathetic fibers) and thendirectly or indirectly prevent or limit the release of norepinephrine atthe nerve presynaptic terminal. As local intracellular or extracellularlevels of the neurolytic agent rise, the drug initially modulates thenerve activity within its therapeutic range to exert a beneficial effecton reduction in norepinephrine spillover; as the drug concentrationcontinues to rise to toxic levels it triggers pre- and/orpost-ganglionic efferent neuronal cell death. At high concentrations,neurotoxicity to afferent and pre-ganglionic neurons that course throughor in the paravertebral gutter is also possible. In one embodiment, thespecificity of the neuromodulatory drug for the post-ganglionic nervesresults in only the sympathetic efferent fibers being targeted. In yetanother embodiment, the neuromodulatory drug targets only thesympathetic afferent fibers. In another embodiment, the drug targetsonly the pre-ganglionic fibers, reducing the extent of denervationsupersensitivity. In another embodiment, such as for applications forthe treatment of angina or ventricular arrhythmia, both the afferent andefferent sympathetic fibers are targeted. In another embodiment, such asfor applications for arrhythmias (atrial, ventricular), it may bedesirable to denervate only the pre-ganglionic sympathetic fibers, thepost-ganglionic sympathetic fibers, or both fiber types. In yet otherembodiments, it may be desirable to denervate the parasympathetic,sympathetic, and/or interneuron fibers in the cardiac intrinsic gangliaand plexi or subsets of neurons thereof. In another embodiment, it maybe desirable to modulate only a subset or subsets of the fibers, by adifferent classification, such as by size and presence or absence ofmyelin. Similarly, it may be desirable to modulate C fibers(nonmyelinated, pain, nonlocalizing ache), temperature, touch,postganglionic autonomic), B fibers (preganglionic autonomic), orA-delta (Pain, fast-localizing, temperature, firm touch), A-gamma(muscle spindle stretch), A-beta (light touch and pressure), and A-alpha(somatic motor and proprioception) fibers differentially.

Reducing norepinephrine release can be achieved, for example, byblocking or inhibiting the action potential of the post-ganglionicneuron, blocking the release of acetylcholine from the pre-ganglionicsympathetic neuron, blocking the acetylcholine receptors on thepost-ganglionic neuron, blocking the action of acetylcholine-induceddepolarization, blocking the synthesis of norepinephrine (norE),blocking the transport of norE, blocking vesicular norE release andvesicle cycling, competing with or replacing norE transport intovesicles, depletion of neurosecretory vesicle content, modulating thecalcium currents. This can result in a reduction on local norepinephrinelevels at the tissue level and may translate to a reduction innorepinephrine spillover from the organ.

Alternatively, the neuromodulatory agent may be delivered to the neuronswithin the therapeutic window and provide a sustained block ofnorepinephrine release or neuronal activity, resulting in a long-lastingbut reversible chemical sympathectomy without denervation of the nerve.In one embodiment this can be achieved by sustained release of apresynaptic alpha-2 receptor agonists such as dexmedetomidine or thenon-selective alpha blocker phentolamine. In another embodiment, thiscan be achieved with the sustained release of reserpine, a VMAT-2receptor antagonist, a catecholamine depleting agent. In anotherembodiment this can be achieved with pentolinium, a nonexcitatoryganglionic blocking agent. In other embodiments, the co-transmittersneuropeptide Y or histamine may also be reduced. In another embodiment,a local anesthetic, such as bupivacaine, results in local anestheticeffects. At higher concentrations, these agents result in neurolysis ofthe sympathetic visceral efferent (and also afferent) nerves innervatingthe thorax. Generally, because these agents are functioning through anon-excitotoxic mechanism of cell death, longer duration exposure maynecessary to achieve neuronal degeneration.

In yet another embodiment, neuromodulatory agents can be delivered atthe nerve terminals or synapses in the periphery at the target tissue,such as the lung or the heart. In some embodiments, the greatestproportion of cell receptors for the drugs are found at the nerveterminal or synapses. In other embodiments, the drug can cross thecytoplasmic membrane or is taken up through endocytosis orreceptor-mediated endocytosis and transported retrogradely to the cellbody, in this case the sympathetic ganglia to trigger apoptosis orneuronal cell death. The following drugs may be used as neuromodulatoryagents, or, at higher concentrations, they may act as neurolytic orneurotoxic agents.

Action Potential Blockers.

Drugs that block the depolarization and effectively prevent the nervefrom reaching a threshold to trigger an action potential or drugs thatare hyperpolarizing or prolong the hyperpolarization of the neuronalcell membrane may be effective at preventing or reducing the release ofnorepinephrine at the synapse. These drugs may result in an inhibitorypostsynaptic potential or IPSP.

Ion Channel Modulation.

Drugs that block calcium channels such as dihydropyridine (DHP)-typeblockers (e.g. nifedipine, felodipine, nicardipine, nimodipine, andamlodipine), and non-hydropyridine blockers (phenylalkylamines (e.g.,verapamil), benzothiazepines (e.g., diltiazem), nonselective agents(e.g., mibefradil, bepridil, flunarizine, fluspirilene, and fendiline).In particular, the neuronal N-type blockers omega-conotoxin GVIA (0.9microM) which blocks NE and histamine release from sympathetic neuronsbut does not alter neuronal NE uptake or storage, or ziconotide, orT-type blockers such as amiloride (500 microM) which modulate dorsalroot ganglion activity, L-type blockers like ethanol, verapamil, orcombination L- and T-type antagonists such as lomerizine, P-, Q- andN-type blockers such as omega-grammotoxin SIA or omega-agatoxin IVA maybe employed. Ranolazine, which blocks the late inward sodium current,may be beneficial if delivered locally to the sympathetic ganglia sinceit blocks the neuronal sodium channel and may have a role in relativelyreducing sympathetic activity relative to parasympathetic. Drugs thatactivate potassium channels hyperpolarize and stabilize the cellmembranes, reducing calcium entry, preventing vasoconstriction may beemployed. These include, for example, diazoxide, minoxidil, nicorandiland pinacidil. Na+/H+ exchange inhibitors such as benzamil, cariporide,sabiporide, amiloride or the more specific derivatives,dimethylamiloride or ethylisopropylamiloride, reduce neuronal cellexcitability, and markedly attenuate norE overflow which may be desired.Drugs that block sodium channels may be selected including 1,-8-cineole.Hyperpolarization-activated cyclic nucleotide-gated channels (HCN)inhibitors, such as ivabradine, lamotrigine, gabapentin, propofol, andlidocaine may be employed. The anticonvulsant valproic acid has beendemonstrated to hyperpolarize sympathetic ganglia and triggerneurotoxicity at higher concentrations.

Sigma Receptor (σ1Rs) Agonists.

Sigma receptor agonists may rapidly inhibit or block all calcium channelsubtypes found on the cell body of the sympathetic neurons (N-, L-P/Q-and R-type calcium channels) at the sympathetic ganglia or intrinsicganglia (e.g. intracardiac), accelerate calcium channel inactivationrate, and shifted the activation toward more negative potentials.Sigma-1 receptor agonists include haloperidol, ibogaine,(+)-pentazocine, and 1,3-Di-O-tolylguanidin (DTG) as well as berberine,citalopram, dextromethorphan, dehydroepiandrosterone (DHEA) andpregnenolone, fluoxetine, igmesine, ketamine, methamphetamine,methoxetamine, noscapine, phencyclidine, novocaine, prilocaine and otheropioids buprenorphine, tramadol. Buprenorphine has been reported to beused in Ganglionic Local Opioid Analgesia (GLOA) blocks at the stellateganglion for the treatment of upper body chronic pain syndromes.Antagonists to these receptors have also been demonstrated to exertanti-nociceptive actions both centrally and peripherally by modulatingpain hypersensitivity. Amiodarone is a class III antiarrhythmic agentthat has beta blocker-like and calcium channel blocker-like actions,increasing the refractory period via sodium- and potassium-channeleffects, and has demonstrated neurotoxicity. The first generationantipsychotics chlorpromazine and pimozide or second generationless-cytotoxic antipsychotics olanzapine and risperidone, for example,are cytocidal. As with other cytotoxic agents, their cytotoxic potentialis usually after the receptors have been saturated and may be related tocholesterol-related mechanisms and changes in lipid metabolism.

Anesthetics also block voltage-gated sodium (or calcium) channels andthus block nerve activity sympathetic efferent and afferent nerves andmay be employed from the amnio-amides, amino-esters, or other group.These drugs have demonstrated cytotoxicity in visceral sensory neurons(sympathetic) and sympathetic efferent (pre- and post-) ganglionicneurons at higher concentrations which can be used to achieve apermanent nerve block. Anesthetics (aminoesters, aminoamides) includeN-butyl tetracaine (37 mM, 1.11% tetracaine-HCl) and other tetracaines,bupivacaine, ropivacaine, ketamine, lidocaine, procaine, iontocaine,chloroprocaine, EMLA, prilocaine, benzocaine, mepivacaine, neosaxitoxin,tetrodotoxin, saxitoxin, prenylamine, Marcaine, lignocaine,levobupivacaine, benzocaine, menthol, and the like. In one embodiment,the procedure is performed under ether anesthesia because these can, insome cases, result in faster depletion of norepinephrine content thanpentobarbitone anesthesia after surgical sympathectomy.

In one embodiment, the local concentration and duration of anestheticexposure can be controlled to permit differential blockade and ordifferential neurotoxicity. For example, the type B fibers (e.g.sympathetic efferent) may be blocked followed by the type C fibers (e.g.sympathetic or somatic afferent). Many anesthetics have multipleinhibitory effects such as lidocaine, which is also a nicotinicacetylcholine receptor blocker. At higher concentrations necrotic andapopotic (lidocaine, amitriptyline) cell death may be triggered by othermechanisms. In one embodiment, 2% lidocaine is delivered locally. Inanother embodiment, 5% bupivacaine is delivered locally. In anotherembodiment, prilocaine is administered to inhibit nerve firingimmediately and may also inhibit the NET transporter.

Drugs that induce, potentiate, or increase the persistence ofhyperpolarization via the 5-HT1 receptor such as 5-hydroxytryptamine,8-OH-DPAT and 5-Carboxamidotryptamine (5-CT), haloperidol or ketanserinmay be employed. This mechanism may also result in a reduction inacetylcholine from pre-synaptic pre-ganglionic sympathetic efferentneurons. Other agents that reduce the synaptic transmission insympathetic ganglia include lysergic acid diethylamide, methysergide,and chymotrypsin. Other agents that may be of interest are drugs thanenhance the uptake of norepinephrine into the nerve.

Vesicular monoamine transport (VMAT) inhibitors, and VMAT-2 inhibitorsin particular, are another class of compounds that may be used tomodulate or chemodenervate. VMAT 2 inhibitors include reserpine (RES,also blocks VMAT-1), bietaserpine, ketanserin, tetrabenazine (TBZ),phenylethylamine, MDMA (Ecstacy), N-methyl-4-phenylpyridinium (MPP+),non-hydrolysable GTP-analogue guanylyllimidiodiphsphate GMP-P(NH)P andVMAT-1 inhibitor fenfluramine. These drugs belong to the class of indolealkaloids and also include ajmaline, mediodespidine, desperidine,syrosingopine and rescinnamine. In particular, reserpine depletes thegranular uptake and storage of catecholamines through near irreversiblebinding to VMAT-2, such as norepinephrine, and 5-hydroxytryptamine(5-HT) and does not excite sympathetic efferent post-ganglionic neurons,leading to a chemical sympathectomy. Resperine may be delivered locallyat doses of, for example, about 0.1 to about 10 mg, about 0.5 to about 5mg, about 1 to about 2 mg per injection at a concentration of betweenabout 0.1 to about 1 mg/ml, such as 0.02 to 0.5 mg/ml, or 0.03 to 0.25mg/ml.

Nondepolarizing Ganglionic Blockers.

Nicotinic receptor blockers competitively block the action ofacetylcholine on nicotinic receptors or block the ion channel that isgated by the nicotinic receptor. In one embodiment, nicotinic receptorblockers can be delivered locally to the sympathetic nervous system,such as the ganglia themselves, and block efferent neurotransmissionirrespective of the neurotransmitter released at the nerve endings (e.g.norepinephrine, acetylcholine, histamine, NPY). Ganglionic blockersinclude chlorisondamine, tetraethyl ammonium (TEA), methyldopa,neostigmine, pempidine hydrogen tartrate, hexamethonium, decamethonium,mecamylamine, methyllcaconitine trimethaphan camsylate, trimetaphancamphor sulfonate, rocuronium, ibogaine, 18-methoxycoronaridine,dextromethorphan and pentolinium tartrate, and otherpolyalkylpiperidines and their derivatives. Other agents includemonoxidine, amantadine, erysodine, tubocurarine chloride, varenicline,atracurium besylate, dehydronorketamine, ketamine, alpha-conotoxin,alpha-bungarotoxin and their pharmaceutically acceptable salts andoptical isomers, and high-concentrations of bilirubin. In oneembodiment, hexamethonium was injected locally. Alpha7-nicotinicacetylcholine receptor (a7-nAChRs) antagonists may be particularlysuitable for the application such tetrodotoxin, nitro-L-arginine, andguanethidine.

Agonists of muscarinic acetylcholine receptors, also found onsympathetic nerves, are responsible for inhibitory post-synapticpotentials (IPSPs) and slow excitatory (EPSPs) under certain conditionssuch as atropine or scopolamine or other drugs that are inhibitory suchas γ-aminobutyric acid GABA or GABA agonists (e.g. GABA_(B) agonists),or baclofen. Alternatively, some antagonists of muscarinic receptors mayalso be selected to reduce nerve transmission, such as pirenzepine.Aromatic amino acid hydroxylase inhibitors, that inhibit tyrosinehydroxlase activity including halogenated phenylalanines, 3-alkylmethyltyrosines, 3-substituted alpha-methyltyrosines, and3-alkyl-methyltyrosines or antibodies to tyrosine hydroxylase, orantihypertensive drugs that modulate TH activity, such as anti-DBH,hydralazine, may be employed. Drugs that degrade catecholamines or drugsthat inhibit the biosynthesis of norepinephrine as anti-dopaminebeta-hydroxylase (anti-DBH) or DBH inhibitors such as nepicastat, orhydralazine may be employed. MAO enzymes' primary role is the metabolismof exogenous amines, control of neurotransmitter levels andintracellular amine stores and in the catabolism of neurotransmitters inthe periphery. MAO-A preferentially oxidizes serotonin andnorepinephrine, whereas MAO-B oxidizes phenylethylamine (PEA), withdopamine and tyramine being substrates for both isoenzymes.

There are several other classes of drugs of interest that modulatenorepinephrine release. Several agents that modulate norepinephrinerelease indirectly include 1) Autoinhibitory Alpha-2 adrenoreceptoragonists, mimicking the action of norepinephrine, are located primarilyon the presynaptic postganglionic nerve ending and inhibit the furtherrelease of norepinephrine from the neuron and may reduce the neuronalsupersensitivity. These agents include dexmedetomidine, oxymetazoline,rilmenidine, moxonidine, agmatine and clonidine and non-selectivephenoxybenzamines. The latter agents also act on the imidazoline (1)receptors. Non-selective alpha blockers, acting on alpha-2 receptorsinclude phentolinamine, an irreversible phenoxybenzamine. 2) Nucleosidetransport inhibitors. For example, draflazine, which increases adenosineconcentrations in the synaptic cleft which in turn inhibitnorepinephrine release through stimulation of pre-synaptic receptors, 3)Autoinhibitory H3 histamine receptor agonists such as(R)-alpha-methylhistamine, which inhibit the co-release ofnorepinephrine and histamine. 4) Serotonin (5-HT) acting on anautoinhibitory receptor, has also been demonstrated to inhibitnorepinephrine release, 5) Presynaptic imidazoline receptor agonistswhich inhibit the release of norepinephrine including antazoline,cirazoline, idazoxan, 6) Guanidines such a guanidine chloride andderivatives, aganodine, arginine, and saxitoxin have been demonstratedto inhibit norepinephrine release from sympathetic nerves, 7)non-depolarizing neuromuscular blocking drugs that also modulatesympathetic efferent and afferent nerves including Cistracurium besilate(Nimbex), one of the isomers of atracurium, 8) hormones such as estrogen(beta-estradiol) which reduce NGF protein and TH protein content andreduced sympathetic neuron survival, and 9) sustained release oftyrosine hydroxylase inhibitor metirosine (alpha-methyl-p-tyrosine orAMPT) that has been demonstrated to reduce the release of norepinephrineand epinephrine, 10) In addition, angiotensin type II receptor blockerssuch as losartan may inhibit sympathetic nerve activity 12) In anotherembodiment, blockers of the p75 receptors and tropomyosin-relatedreceptor tyrosine kinases (Trk), such as TrkA, reduce adrenergic outputand neuronal survival. Blocking the activation of TrkA by NGF preventsthe potentiation of an excitatory noradrenergic transmission at theneuron-myocyte synapse. Similarly, stimulating the p75 neurotrophicreceptor promotes inhibitory acetylcholine release. 13) Adenosine andadenosine agonists, activates K+ and Cl-conductances, limitssynaptically evoked depolarization and Ca2+ influx, directly protectingneurons against Ca2+ mediated overload but at high concentration causeapoptotic cell death.

Drugs that improve the reuptake of norepinephrine from the synapticcleft directly or indirectly include perindopril, candesartan, andvalsartan, or through modulation of dynamin-mediated endocytosis andvesicle cycling. Another approach is to reduce the activity of thepre-ganglionic neurons. Alfuzosin, (10-40 mM) the alpha-1 receptorantagonist, reduces sympathetic pre-ganglionic sympathetic nerveactivity and thus reduces the post-ganglionic nerve firing andnorepinephrine spillover. In yet another embodiment, p75 neurotrophinreceptor (p75NTR) agonists, such as through proNGF, NGF, LIF, IL-6,IL-1, TNF-alpha, BDNF or proBDNF may denervate the sympathetic gangliaand block sympathetic sprouting to the DRG.

In another embodiment, it is desirable to prevent the activation ofvisceral afferent nociceptive C fibers that either travel with thesympathetic or parasympathetic nervous system, so as to block or reducethe transmission of pain. Since many of these fibers travel with thesympathetic nervous system through the sympathetic chain, therapiesdesigned to modulate this class of neurons alone or in combination withsympathetic efferent fibers is desirable. NGF is a survival factor forboth developing afferent and sympathetic efferent nerves, and hasrecently been demonstrated to play an important role in the generationand perpetuation of neuropathic, inflammatory and ischemic pain andhyperalgesia across the afferent (somatic/visceral) and sympatheticefferent neurotransmission. In one embodiment, an agent that blocks orantagonizes NGF or blocks its binding to TrkA is administered. Drugsthat reduce the survival and/or axonal outgrowth after injury, such asthrough sequestration or reduction in nerve growth factor (NGF) levels,may be desirable. These include neurotrophic Tyrosine kinase receptor A(TrkA or NTRK1) antagonists that sequester NGF via the TrkA domain 5,antibodies to TrkA or NGF, such as local anesthetics.

In another embodiment, a patient may be prescribed reserpine and/or one,two, or more therapeutic agents as disclosed for example herein orally,intravenously, subcutaneously, intramuscularly, transdermally, orthrough another route of administration for one to three days prior tothe procedure in order to lower their systemic norepinephrine levelsprior to the procedure. In another embodiment, the patient continues totake reserpine or other therapeutic agent(s) for a specified time suchas 30 to 60 days after the procedure.

In another embodiment, delivery of leukemia inhibitory factor (LIF),interleukin-6 (IL-6) or ciliary neurotrophic factor (CNTF) will triggerin a switch from adrenergic nerves to a cholinergic phenotype, reducingthe release of norepinephrine. In another embodiment, inhibitors of LIF,IL-6 and CNTF may be delivered to reduce the sympathetic nerve sproutingto form connections with the dorsal root ganglion. In anotherembodiment, blocking the sodium Navv1.6 channel reduces pain, sensoryneuron excitability and sympathetic sprouting. In another embodiment,beta-3 adrenoreceptors antagonists are delivered to the regioncontaining the DRG to modulate the sympathetic post-ganglionic activity.

In indications in which acute and subacute control over local orsystemic neurotransmitter levels is not necessary or desirable,alternative neuromodulatory agents can be employed to modulate thenervous system, particularly the sympathetic nervous system. Drugs thathyperpolarize cells to temporarily cause hyperexcitability through theincreased dumping of neurotransmitter only to later cause the nerve todegenerate are of particular interest. These include tricyclicanti-depressants and other anti-depressants, and other nonspecificagents such as those that temporarily increase the levels ofneurotransmitter in the synaptic cleft before blocking and reducingneurotransmitter levels. These agents can be used in combination withanesthetics to reduce or eliminate the norepinephrine release.Secondarily, agents that result in excitotoxic cell death, in whichneurons are damaged or killed by excessive stimulation are described.

Alcohol and phenol (carbolic acid, monohydroxybenzene) are both commonlyused neurolytic agents. Alcohol causes an immediate progressive burningparesthesia that lasts several hours but a wide range of ethanolconcentrations are effective at destroying nerves through extraction ofcholesterol and phospholipids and subsequent sclerosis. Concentrationsabove 50% are well established to result in neurolysis, such as about75%, 80%, 99% or 100%. One-hundred percent ethanol has been demonstratedto completely destroy the cell bodies and axons of sympathetic, sensoryand motor neurons but come with a higher risk of adjacent neuritis.Phenol has mild anesthetic properties and causes a focal hemorrhagicnecrosis and dissolves axons and Schwann cells inside the basal lamina,resulting in damage to the entire endoneurium. Regeneration in theperiphery may begin in 2 weeks in preclinical studies. The drug can beinjected at, for example, between 3 and 10%, more typically between 6.7%to 7% in oil or glycerol, such as Phenol-Aqua (7%) or phenol-glycerol(5%). Higher concentrations have been applied, such as about or at leastabout 10%, 25%, 50%, and 75%, such as between about 10-50% phenol inethanol is desirable in some cases. Both produce severe burning painimmediately upon injection which may last about a minute. Glycerol is ananhydrous less toxic alcohol with weaker penetration, less extensiveneuronal damage and faster regeneration than alcohol and phenol. Iohexol(30%) may also be employed. Alternatively, sodium tetradecyl sulfate(STS), an anionic surfactant and sclerosant drug with detergentproperties may be selected.

By incorporating these readily available neurotoxic agents into aformulation that will slow or control their spread, adverse events andcomplications arising from their use can be limited. In one embodiment,ethanol is incorporated in the gel as a solvent for the neuromodulatoryagent that is delivered. In another embodiment, there is noneuromodulatory active agent and ethanol alone provides the neurolyticeffect but its spread is controlled by its containment within aformulation. In one embodiment, after delivery, the rapid tissueabsorption of ethanol into the surrounding hydrophobic neurons andadipocytes causes the liquid formulation to gel.

Norepinephrine reuptake inhibitors (NRIs) and less specificnorepinephrine serotonin reuptake inhibitors (SNRIs) (and selectiveserotonin/5-hydroxytryptamine reuptake inhibitors (SSRIs) and dopaminereuptake inhibitors) block the reuptake of norepinephrine at thesynaptic cleft thereby increasing and sustaining the action ofnorepinephrine at the nerve terminal in the heart and other tissues.Norepinephrine uptake transporters (NET) includes Uptake 1, present inthe neurons and lung pulmonary endothelial cells and uptake 2transporter, present in the myocardium. Reuptake inhibitors includeguanethidine, 1-methyl-4-phenyl-pyridinium ion (MPP⁺) and Oxidopamine or6-hydroxydopamine (6-OHDA), alpha-methyldopa, bretylium tosylate,guanacline, bethanidine and debrisoquine, desipramine, nisoxetine,ritanserin, setoperone, volinanserin, duloxetine, citalopram,fluvoxamine, zimeldine, sibutramine, Levomilnacipran, debrisoquine,lobeline and amezinium. Dopamine reuptake inhibitors include GBR-12909and amfonelic acid. Many of these agents also function as MAO inhibitorsto prevent norepinephrine deamination and some as a VMAT agonist.Although not a reuptake inhibitor, alkaloid cocaine interferes withUptake-1. Guanethidine (1-2 mg/ml) is particularly interesting in someembodiments because it can both increase the norepinephrine in thesynaptic cleft (transient sympathomimetic) initially through NET1activity but also acting as a monoamine depleting agent, and blocksadrenergic transmission. High or sustained doses lead to neuronal celldeath in both efferent and afferent nerves, such as capsaicin-sensitiveprimary sensory nerves. Preferably, these agents are delivered to nerveterminal or peripheral synapse of the post-ganglionic sympathetic nervein the heart, lung, or tissue innervated by post-ganglionic sympatheticefferent nerves. At high concentrations, these agents result inimmunotoxic NK- and mononuclear-cell mediated death as can be seen bydegeneration of sympathetic ganglia in the sympathetic chain.

Anti-Depressants.

In another embodiment, the neuromodulatory agent is an anti-depressantsuch as bupropion, doxepin, desipramine, clomipramine, imipramine,nortriptyline, amitriptyline, protriptyline, trimipramine, tianeptine,fluoxetine, fluvoxamine, paroxetine, sertraline, phenelzine,tranylcypromine, amoxapine, maprotiline, trazodone, venlafaxine,mirtazapine, their pharmaceutically active salts and/or their opticalisomers. In a very preferred embodiment, the anti-depressant is eitherbupropion or a pharmaceutically acceptable salt thereof, ornortriptyline or a pharmaceutically acceptable salt thereof. Bupropion,desipramine and imipramine are also ganglionic blocking agents(nicotinic) and at higher doses is toxic to afferent and efferentnerves.

Microtubule disrupting agents or cytoskeletal drugs that interact withactin or tubulin may also be used to denervate neurons such asphalloidin, cytochalaisin D, Latrunculin, colchicine (1 and 10 microM),demecolcine, jasplakinolide, nocodazole, paclitaxel (taxol), andvinblastine. Other potential approaches include inhibition ofphophoinositide 3-kinase (PI3K), serine-threonine protein kinase B(Akt), extracellular signal-regulated kinase (ERK) pathway, the P38mitogen activated protein kinase pathway (MAPK).

Cholesterol oxides (PMID 9566506) cause rapid cell sympathetic gangliacell death in vitro at concentration of 4 ug/ml (10 uM) within 36 hours.The most potent of these 25-OH-cholesterol has demonstratedneurotoxicity across a range of cell types.

MAO-A and COMPT inhibitors, including tyramine, clorgyline, paragylineand 3,5-dinitrocatechol, Ro 41-1049, selegiline, tranylcypromine mayresult in excitatory chemical sympathectomy if delivered in high enoughlevels.

Immunosympathectomy can be achieved with Anti-Nerve growth Factor(anti-NGF, Tanezumab, Fulranumab), auto-immune sympathectomy withAnti-Dopamine Beta Hydroxylase (DHIT), DBH or Anti-acetylcholinesterase(Anti-AChE, immunotoxin sympathectomy with OX7-SAP, 192-SAP IgG, DBH-SAPor DHIT. Toxins such as botulinum toxin (BOTOX, DYSPORT type A throughG, such as described, for example, in U.S. Pat. No. 6,743,424 toDonovan, which is hereby incorporated by reference in its entirety),tetrodotoxin, neosaxitoxin, may also be effective.

Efferent Nerve Degeneration.

Botox can be advantageous in some embodiments for delivery to thesympathetic chain because it preferentially targets the pre-ganglionicsympathetic efferent nerves by blocking the release of acetylcholine.Blocking the sympathetic pre-ganglionic stimulation of post-ganglionicnerves has been demonstrated to dramatically reduce norepinephrinerelease from the post-ganglionic nerves. Botox injections typically lastbetween 3 to 6 months, providing a sustained reduction in efferent nerveactivity during this time. Furthermore, denervation of pre-ganglionicfibers, while leaving the post-ganglionic fibers intact results inreduced denervation supersensitivity (upregulation of beta-adrenergicreceptors in the heart). As with all drugs, ‘off-target’ effects onpost-ganglionic and afferent nerves are likely, although the agent willlikely have a less powerful effect on these nerves.

Afferent Nerve Degeneration.

High concentrations of capsaicin result in a stimulatory denervation ofafferent nerves with small diameter soma (dark B-type)>intermediatediameter soma (light-A type)>type C fibers>thinly myelinated Aδ fibersand therefore may be used to provide short-term degeneration of sensorysomatic or visceral fibers. Alternatively, resiniferatoxin (RTX)underway for trials for intrathecal administration for intractable pain,may also be suitable for applications in the paravertebral gutter as itis a highly selective agonist of the TRPV1 receptor and can selectivelyablate afferent neurons. Some anesthetics have relatively selectivityfor C fibers and can potentially be administered at a concentration thatablates afferent fibers but only blocks other fibers types. In someembodiments, the delivery of excitotoxins such as kainic acid (0.5nmol/ul), kainate/kanamycin, or N-methyl-D-aspartic acid (NMDA, 6.8nmol/ul) and NMDA subtypes, okadaic acid, GM1 ganglioside, quisqualateor a-amino-3-hydroxy-4-isoxazoleproprionic acid (0.54 nmol/ul) can beapplied that have been demonstrated preclinically to target onlyafferent, not efferent fibers. These agents result in considerable lossof cell bodies but spare axons and appear to be selective for thedenervation of vagal afferent neurons but only stimulatory to theafferent dorsal root fibers.

Drugs—Gene Therapy.

Alternatively, a gene therapy based approach to silencing nerves can beused to effectively halt neural activity of a pathway. For example, DNA,RNA, RNAi, and/or siRNA can be delivered to send a neuron into apro-apoptotic pathway, to deliver a light-sensitive protein so thatlight can halt neurotransmission in a cell, such as described in U.S.Pub. No. 2013/0225664 to Horsager et al., which is hereby incorporatedby reference in its entirety. Neurotrophic factors (e.g. GDNF, BDNF, orNGF) or neurotrophic factor receptors (e.g. TrkA or p75 low affinity NGFreceptors) can be knocked out or deleted. Alternately, the phenotype ofneurons can be altered such as from noradrenergic to cholinergic orneurotransmitter synthesis can be up or down regulated through changesin transcription and translation factors. Examples of proteins whoseexpression can be directly or indirectly up- or down-regulated includeleukemia inhibitor factor, phenylethanolamine-N-methyl transferase(PNMT), tyrosine hydroxylase (TH) or DOH.

Modulating supersensitivity may be desirable specifically pre- orpost-junctional supersensitivity, in which the responsiveness of cellsis characterized by a leftward shift of concentration-response curvesfor agonists.

Suicide Axoplasmic Transport (Retrograde).

In yet another embodiment, a neuromodulatory agent can be delivered atthe distal nerve terminals and retrogradely transported to the gangliato modulate the nerve. In this manner, nerves innervating a targettissue or organ can be selectively denervated, such as, for example,with Adriamycin or Epirubicin. In one embodiment, 0.05 to 1 mg ofAdriamycin (doxorubicin) can be delivered to the heart, lung, and greatvessels of the thorax to selectively destroy non-motor afferent andefferent sympathetic and vagal fibers, providing an avenue to deliverthe cytotoxic drugs to nerves away from the intrathecal space. Thesetissues include the pericardial sac, the epicardial fat pads, the nervestraveling along or across the coronary arteries, coronary veins,coronary sinus, the nerves traveling around the pulmonaryarteries/veins, the pulmonary artery trunk, the aorta, the bronchialarteries/veins or lung root/hilum. These agents may be delivered througha transvascular or percutaneous or other minimally invasive approach. Ifperformed carefully, high local concentrations of Adriamycin can bedelivered to the sympathetic chain with careful avoidance of theintrathecal space, to achieve post-ganglionic sympathectomy. This celldeath can also be achieved with other retrogradely transported agentssuch as Ricinus communis agglutinins and highly toxic lectins forexample. Alternatively, neurotoxic or neurolytic drugs can be conjugatedto retrogradely transported peptides or proteins, such as wheat germagglutinin (WGA), dextran, horse radish peroxidase (HRP) for rapidaxonal transport to the perikaryon from a nerve terminal orcrushed/transected nerve. In another embodiment, the retrogradetransport can be used to deliver drugs that support neuronal survivaland/or regeneration. In another embodiment, viruses than are known to betransported retrogradely and transsynaptically can be used to deliverneuroprotective agents from the periphery directly to the target cellsin the central nervous system, such as the hypothalamus. In oneembodiment, the retrograde transsynaptic tracer pseudorabies virus (PRV)coated nanoparticle loaded with NGF can be delivered to theparavertebral gutter for delivery both locally and to central nervoussystem. For example, agents can be delivered into the paravertebralgutter that are then taken up by pre-ganglionic neurons and transportedtransynaptically to the locus coeruleus for the treatment of Parkinson'sdisease. These agents may also provide for improved local survival ofneurons within the sympathetic chain, as these patient's also sufferfrom loss of cardiopulmonary sympathetic nerves.

Double Crush or Synergistic.

In some embodiments, nerves may receive a “double crush” in which two,three, or more therapeutic agents or factors, in series or in parallel,lead to effective neuroablation through, in part, a synergistic effect.The first factor may be the presence of an existing precondition such asneuropathy or diabetes prior to receiving the second ‘crush’, theneurolytic agent. In another embodiment, the first crush may be asystemically administered agent, (whether delivered, for example,orally, intravenously, intraarterially, intraperitoneally or as aninhaled agent) that lowers the threshold for neurotoxicity before alocal agent is delivered to ablate the nerves in the region. In oneembodiment, reserpine is administered systemically, and then aneurolytic agent, such as lidocaine, is administered locally, asdescribed, for example, in U.S. Pat. No. 4,029,793 to Adams et al. orU.S. Pat. No. 7,928,141 to Li, both of which are incorporated byreference in their entireties. In another embodiment, an anestheticagent is delivered first to block the nerves and reduce the pain, andthen subsequently a neurolytic agent is delivered that actssynergistically with the anesthetic agent to locally denervate theneurons. In another embodiment, a local agent is delivered and coupledwith a mechanical or thermal signal to cause more complete neuronal celldeath, such as a neurolytic agent combined with high-frequencyultrasound or radiofrequency ablation. In another embodiment, thesynergistic effect may allow for a reduction in the dose orconcentration of one or both agents, thereby reducing systemic toxicity.

In another embodiment, other drugs with known neuromodulatory effects,many with transient or acute excitotoxic effects, include, for example,glutamate, glutamine, polyglutamine, isoniazid, crotoxin, taipoxin,phenylephrine, tryptamine or 5-hydroxytryptamine, chlorpromazine,clozapine, doxorubicin (TRPV1), NMDA, MPTP, chlorpromazine and otherphenothiazines, ampicillin, N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine(DSP-4), lanthanides, yohimbine, nicotine and lobeline and amphetamine(mixed agonist-antagonists), nicitinamide and nicotinic acid andderivatives, lectins, trimethyltin (TMT), NSAIDs such as indomethacin,nitrosoureas such as streptozotocin, streptomycin, gentamycin,bleomycin, 6-hydroxydopamine (100 mg/kg sc), kainite, quinolinic acid,phenytoin, bupropion, thalidomide, quinolinate, fluoroquinoloneantibiotics such as moxifloxacin, levofloxacin, and ciprofloxacin,varatum alkaloids such as proveratrine or veratridine, vinca alkaloidssuch as vincristine, bortezomib (glove and stocking peripheralneuropathy), rotenone (pesticide), yessotoxin (increase in cytosoliccalcium), brevetoxin (L-glut and L-asparate), the fluoroquinolonesincluding ciprofloxacin, gatifloxacin, gemifloxacin, and levofloxacin;myelin fludarabine, methotrexate, vinblastine sulfate (0.4 mg/kg sc)vincristine, cisplatin, oxaliplatin, ormaplatin, gentamycin,gemcitabine, sorafenib, angiotensin II agonists, saralasin, bleomycin,taxol/paclitaxel, L-arginine, phenytoin, caspace, caffeine, captopril,paclitaxel which induce ceramide synthesis include chemotherapeuticagents, gamma interferon, matrix metalloproteinases, and anandamide.Corticosteroids such as prednisone, methylprednisolone, triamcinolonediacetate, triamcinolone acetonide, or betamethasone can also beutilized. Drugs which block GABA-ergic transmission of sympatheticganglia such as bicuculline and metrazol, VMAT-2 agonistmethylphenidate, amphetamine, the powerful toxic lectin ricin,ergotoxine or ergotamine or ergotoxine derivatives (ergocristine,ergocornine, ergocryptine, methysergide) paralyze the sympatheticnervous system or cabergoline, pergoline or lisuride, gambierol,pyrethroids, ivabradine, mibefradil, nicorandil, trimetazidinequinapril, losartan, droperidol, tramadol, labetalol, spiperone,picrotoxin, butyl aminobenzoate, HA H3 receptor antagonist thioperamide,opipramol, pentazocine, lacidipine, 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors including mevastatin and lovastatin;rimcazole, panamesine, rimcazole, metaphit, tizanidine, apraclonidine,oxaprotiline, and spermine are some examples. Alternatively, sustainedrelease of fast anterograde transport blockers has been implicated inacrylamide and gamma-diketone-mediated, and 2,5-hexanedione (2,5-HD)nerve degeneration.

Other non-pharmacologic chemical agents include salicylic acid (10% inethanol), menthol, isotonic dextrose, hypotonic saline (e.g.,half-normal saline or less, or dextrose in water), hypertonic saline(10%, 1.7M, 100 mg/ml) severe pain) or hyperbaric solution (5-8%glucose) which may be effective against C-fibers. Yet other agentsinclude liquid nitrogen and hydrogen peroxide, octanoic acid, methanol,D-limonene, kainic acid, domoic acid, diethyl ether, andL-2-chloropropionic acid.

Similarly, many of these agents may initially increase neurotransmitterlevels at the synaptic cleft but rapidly halt neurotransmissionresulting in catecholamine depletion at lower doses and then causedegeneration at higher doses possibly through an immune relatedmechanism or cause an initial upregulation in neurotransmission followedby neurodegeneration. Further examples of therapeutic agents that can beutilized with systems and methods as disclosed herein can be found, forexample, in U.S. Pat. No. 6,932,971 to Bachmann and U.S. Pub. No.2006/0280797 to Shoichet et al., U.S. Pub. No. 2015/0132409,2015/0202220, U.S. Pat. No. 8,975,233, U.S. Pat. No. 9,056,184 to Steinet al., U.S. Pub. No. 2013/0252932 and U.S. Pat. No. 9,011,879 toSeward, all of which are incorporated by reference herein in theirentireties.

In some embodiments, it can be desirable to protect a first populationof nerves adjacent or in proximity to another second population ofnerves that are receiving a neuromodulatory therapy or undergoing someother treatment. In one embodiment, the soma, ganglia, plexi, thatrequire neuroprotection can be surrounded with a neuroprotectivebiocompatible ‘blank’ gel in which the neuroprotection is provided bythe compliance of the gel with the tissue and the mechanical barrier ofdrug diffusion through the gel or formulation. In this manner,neurolytic or neurotoxic agents can be delivered alone or in combinationwith a gel the adjacent tissue while protecting other criticalstructures or tissues. The hydrogel may also protect other vitalstructures from chemical, thermal, or mechanical damage. Anotherembodiment involves the delivery of a neuroprotective agent or agentthat antagonizes or attenuates the effects of the neurolytic agentwithin the gel. Like combinations with a neurolytic agent, delivering agel with a neuroprotective agent that is retained in the gel and haslimited spread to the regions in which the neurolytic agent is deliveredcan be desirable. For example, a neuroprotective agent can be applied tothe nerves that it is desired to spare directly or in a sustainedrelease formulation, such as a hydrogel. This procedure can be performedpercutaneously or endovascularly prior to the injection of a neurolyticagent either alone or in a hydrogel. This may be performed through thesame delivery effector such as a needle, such as through a double lumenwith two exit ports facing opposite each other or another angledorientation with respect to the sidewall of the catheter. In someembodiments, delivery of the hydrogels may be performed through the samelumen but the gels are injected serially with the blank orneuroprotective-gel delivered first followed by administration of theneurolytic gel or vice versa. In one embodiment, the delivery of theneuroprotective agent/gel can be delivered in one location through aneedle or lumen and then the needle or lumen can be rotated and oriented180° (such as rostral followed by caudal) to deliver the neurolyticagent/gel to a second location to the nerves it is desired to ablate.For example, it may be desirable in some embodiments to ablate orneuromodulate only the T1 sympathetic ganglia and below. Because 80% ofthe time the T1 ganglia is fused completely or partially with theinferior cervical ganglion, it may be desirable to deliver aneuroprotectant gel or blank gel at the 1^(st) rib to the inferiorcervical ganglia through an ultrasound- or CT- or other image-guidedapproach. This guidance, for example, may be done utilizing one of theanterior approaches to access the stellate ganglion, as performed withstellate ganglion block. After this, either through the same lumen orthrough a catheter extended within or over the existing lumen, aneurolytic gel may be administered to the lower half or third of thestellate ganglion, the T1 sympathetic ganglion. In doing so, avoidanceof Horner's syndrome may be possible. Specifically, the lumen can bedirected upward toward the inferior cervical ganglion at the uppermargin of the 1^(st) rib to deliver a blank hydrogel. The lumen can thenbe rotated caudally to deliver a neurolytic-hydrogel to T1 to T4, asdesired. Alternatively, injections of neuroprotectant gel or ‘blank’ gelcan be made into the relevant intercostal spaces to prevent theintercostal nerves against intercostal neuritis, or into the dorsal orventral roots, or into the intervertebral space or the intrathecal spaceto prevent spread to the roots or spinal cord, respectively.

In other embodiments to permit neuroprotection, one group of neurons canbe protected via the distal delivery of agents at their axons or nerveterminals, away from the cell bodies in the sympathetic ganglia. Theneuroprotective agent delivered there may block or reduce the activityof the specific population of nerves that it is desired to protect. Inthis embodiment, the neuroprotective agent and/or gel may be delivereddistally to the targeted neuroablation zone along the axons or nerveterminals to have neuroprotective effects on the soma and axons directlywithin the neuroablation zone. In one embodiment, the agent is ananesthetic and protects the neuron from excitotoxic cell death.Alternatively, the agent may act as a specific antagonist to themechanism of the neurolytic agent that is delivered. The neuroprotectiveagent may, for example, exert an effect for 24-48 hours, the sameduration of the activity of the neurolytic agent at the injection site.Specifically, in the case of the undesirable effect of neuroablation ofthe inferior cervical ganglion causing temporary or permanent ptosiscomponent of Homer's syndrome, the neuroprotective agent can betopically applied or injected into the eyelid to reach the retractormuscle of the upper eyelid, the levator palpebrae superioris muscle. Inanother embodiment, it is desirable not to denervate a given organ whenperforming a chemical sympathectomy. In order to achieve this,injections of the neuroprotective agent are made into the organ capsule(such as the pericardial sac, pleura, or peritoneum, for example, orinto the vasculature suppling the organ or extravascularly to the nervebundles coursing into the organ. This neuroprotection can also beprovided to populations of neurons undergoing mechanical axotomy, suchas in VATS procedures.

Neuroprotective/Neurocounteractive Drugs.

Neuroprotective drugs can be delivered alone locally or distally ordelivered in a gel or formulation to control their spread and direct theagents to the tissue that requires protection. For example, ananesthetic can be delivered to the nerve terminals to preventneurotoxicity that is induced by excitotoxicity, NGF or CNTF candelivered to prevent neurotoxicity from vincristine and Taxol. Otheragents include potassium channel blockers including amiodarone,clofilium and semtilide to counter-act, for example, potassium channelagonists. Similarly, the calcium channel antagonist flunarizine,cinnarizine, diphenylpiperazines protects against neuronal cell death inpreclinical models of axon transection or crush. Dexamethasone oralpha-lipoic acid can be delivered to attenuate the neurotoxiity ofbupivacaine and lidocaine and reduce provide protection to sympatheticneurons from immune-cell mediated necrosis and apoptosis such as withagents like guanethidine. MAO inhibitors have been demonstrated tocounteract the chemical sympathectomy caused by reserpine.Alternatively, a high-K+ environment (greater than or equal to 33 mM),the actions of a VMAT, such as tetrabenazine (TBZ) can be blocked with acatecholamine uptake also helps to prevent sympathetic cell death.Minocycline and deferoxamine mesilate, amifostine, glutathione,diethyldithiocarbamate, Org 2766, curcumin, or vitamin E can preventagainst cisplatin toxicity. Others drugs with recognized neuroprotectiveeffects include the L-type Ca2+ channel blocker, nimodipine (2 microM)has been demonstrated to be neuroprotective in both DRG and CNS, as wellas nifedipine and nilvadipine, metformin, dexamethasone, estrogen(neuroprotective or neurocytotoxic), bupropion, or the MAO-B inhibitordeprenyl, or the adenosine A2A antagonist MSX-3, or topiramate (TPM) andlacosamide which stabilize hyperexcitable membranes, calcineurininhibitors (CNI) include cyclosporin, tacrolimus, and sirolimus. Assuch, in some embodiments, a first agonist therapeutic agent can bedelivered to a first location, and a second antagonist therapeutic agentto the first therapeutic agent can be delivered to a second location.

Neuron Survival or Neuron Regenerative Drugs.

In still other embodiments, neuromodulatory drugs that provide aneuroprotective or neuron survival cues to the sympathetic afferent andefferent nerves are delivered directly or in a gel-based platform toprovide sustained releases of pro-survival, pro-regenerative,pro-differentiation cues. For example, controlled delivery of nicotineto the sympathetic chain, increases NGF production and thus the survivalencourage the survival of afferent and efferent sympathetic nerves forthe treatment of neurogenic orthostatic hypotension (NOH),cardiopulmonary denervation associated with Parkinson's disease (PD),cardiopulmonary denervation associated with diabetes and pure autonomicfailure (PAF). Agents may also indirectly have a beneficial effect onnerves in the CNS, such as the locus coeruleus in Parkinson's disease.Alternatively, the local sustained delivery of L-dihydroxyphenylserine(L-DOPS) can be delivered to the cardiac sympathetic nerves to generatenorepinephrine since these nerves are firing at the appropriate rate.

Dosing

If chemodenervation is desired, the degree of neurotoxicity may berelated to the concentration or dose administered. Generally, thetoxicity increases with a longer duration of exposure above thetherapeutic range. For example, the highest concentration of anestheticused in local nerve blocks is around 2% in some cases. For a neurolyticapplication, the local concentration of lidocaine, lignocaine, ormepivacaine delivered may be about or at least about 5%, or bupivacainemay be about or at least about 1-2%.

Percutaneous Devices

Unmet need: In addition to the complications associated with theuncontrolled spread of agents like ethanol, the paravertebral block(PVB, anesthetic) injections themselves may be associated with anunpredictable clinical spreading pattern that can vary from time to timewithin a given patient. This results in a failure to achieveparavertebral anesthetic block in up to 10% of patients.

A reliable, safe approach to disrupt or block multiple contiguous levelsof the paravertebral gutter can be desirable to prevent the need forguidance and repeat insertion of needle or catheter at each sympatheticchain level. In the case of percutaneous approaches, this wouldsignificantly reduce the pain and anxiety associated with the procedureand potentially procedural complications. The procedure could beachieved with a flowable therapeutic composition, such as a hydrogel insome embodiments. In some embodiments, the paravertebral gutter can beaccessed endovascularly, such as via a wall of the azygous vein in someembodiments, as opposed to transcutaneous paravertebral blocks.

Therefore, in addition to the appropriate selection of neuromodulatoryagent and injectable formulation, the use of an appropriate devicedelivery system to administer the therapy in a safe and efficaciousmanner can be highly advantageous in some embodiments. In someembodiments, injection of the therapy, including but not limited to a) aneuromodulatory agent or agents alone, b) neuromodulatory agentsdelivered in a formulation such as a hydrogel, c) excipients (such asthose from the GRAS list) delivered in a formulation such as a hydrogel,d) solvents delivered in a formulation such as a hydrogel, or e) ahydrogel alone without an active agent, is delivered into theparavertebral gutter or space. The paravertebral gutter can be accessedfrom multiple minimally invasive approaches including both the anterior(T1) and paravertebral approach transcutaneously and an arterial orvenous approach endovascularly, and it can be preferred in some cases todeliver the agent into or toward the anterior region of theparavertebral gutter to permit longitudinal spread of the agent.Alternatively, the paravertebral gutter can be directly visualized aspart of a VATS or surgical procedure and the therapy delivered throughthe pleura into the paravertebral gutter directly or injected into andaround the site after the sympathectomy. The therapy can be deliveredunilaterally or bilaterally during a procedure, such as for example onthe left side first, and then the right side as needed to achievemaximal therapeutic benefit or vice versa, or only the left side or theright side. Alternatively the procedures can be performed in a stagedfashion. In one embodiment, patients receive a stellate ganglion blockor paravertebral block with anesthetic prior to the delivery of theneurolytic-hydrogel to confirm that they are responders and to identifyany challenges with the patient anatomy.

In some embodiments, the injectate is delivered and the travel islimited to within the paravertebral gutter or space. The thoracicparavertebral gutter space (TPGS) is defined between T1 and T12. Astellate ganglion block, lumbar paravertebral block, and lumbar plexusblocks (psoas compartment block) can also be considered types ofparavertebral block. The cervical and thoracic paravertebral space arecontinuous with one another. The thoracic paravertebral and lumbarretroperitoneal paravertebral space may be in continuity viasubendothoracic fascial communication, although in most cases the originof the psoas muscle seals off the thoracic paravertebral space belowT12, rendering the two paravertebral regions succinct (Karmakar et al2011). For descriptive purposes, each segment of the space is limitedsuperiorly and inferiorly by the heads of the corresponding ribs.

TPGS.

The thoracic paravertebral space or paravertebral gutter is awedge-shaped potential space that can be created by fluid distentionwhen a needle is placed next to the vertebral column or anterior to thetransverse process but posterior to the parietal pleura. Theparavertebral space contains the intercostal nerves as they emerge fromthe vertebral foramen, the dorsal rami, the rami communicantes, theintercostal vessels, the sympathetic chain, intermediate ganglia (ifpresent), and loose connective and adipose tissue. The nerves areunsheathed for the most part, allowing for rapid uptake ofneuromodulatory agents. The space is bounded posteriorly by the superiorcostotransverse ligament and laterally the posterior intercostalmembrane, anteriorly by the parietal pleura, medially by thepostero-lateral aspect of the vertebra, the intervertebral disc, and theintervertebral foramen, superiorly by the occiput, inferiorly by thealair of the sacrum. Anteriorly, there is no place for the material toadvance unless the pleura is breached. Lastly, the TPGS can be furthersubdivided into the anterior and posterior segments by the thinfibroelastic endothoracic fascia. The sympathetic chain lies in the moreanterior region of the paravertebral space. In some embodiments, theparavertebral gutter is filled with the neuromodulatory formulation andthe agent spreads within the gutter to reach the target levels. Directinjection into the sympathetic chain and associated ganglia is avoidedin some embodiments as this may limit the spread of the agent to thesympathetic chain itself and not the finer surrounding structures suchas the rami communicantes and intermediate ganglia, if present.

Challenges

However, laterally, the agent can spread into the intercostal space andmedially it can travel through the intervertebralforamen/transforaminally to the epidural space. This is particularlytrue of ethanol injections, which rapidly and distantly spread from thesite of injection. Finally, the prevertebral fascial lies anterior tothe vertebral bodies and can provide a route to administer a formulationbilaterally. In the cervical region, injectate can travel from theinferior cervical/stellate ganglion to the brachial plexus, vagus nerve,recurrent laryngeal, phrenic nerve and inadvertent injections into thevertebral artery and inferior thyroid artery have been reported. In thethoracic region, injection to intercostal nerves resulting inintercostal neuritis, or rarely, injection into the epidural space hasbeen reported.

Blind.

The objectives of some embodiments of the procedure are to 1) deliverthe therapy longitudinally within the paravertebral gutter consistentlyand successfully and 2) to avoid injection of the formulation intocritical adjacent structures such as vessels, organs such as the lungand associated pleura, and lymphatics. This can be achieved with a blindapproach in some patients (or other imaging guidance in otherembodiments as described elsewhere herein). The transcutaneous orpercutaneous approach to the paravertebral gutter is based on theinjections of anesthetics performed today to achieve paravertebral block(PVB). The paravertebral space is approximately 2.7 cm (range 1.7 to4.31 cm) from the skin surface and with a slightly oblique approach thisdistance become 4.4 cm (range 3.5 cm to 6 cm). As illustrated in someembodiments of the method as shown in FIG. 7A, these injections can beperformed blindly or under imaging guidance by advancing a 18-gaugeTuohy needle (800, shown in phantom) 2 to 5 cm lateral to the midlineperpendicular to the skin. The needle 800 passes lateral to the spinousprocess and penetrates the superior costotransverse ligament 518 by aloss-of-resistance technique. Alternately, a needle is advanced tocontact the transverse process upon which it is angled superiorly orinferiorly and advanced 1 to 1.5 cm until loss of resistance to salineis appreciated. A click may be felt as the superior costotransverseligament 518 is penetrated. There is occasionally a gap between thelateral and medial portion of the superior costotransverse ligament 518that prevents the use of a loss of resistance technique to confirm thatthe needle tip is in the right location. The needle 800 is then slightlywithdrawn and redirected cephalad at a 45 degree angle to the skin forup to 1 to 1.5 cm deeper than the depth of the bone contact. Thecatheter 804 is then inserted through the needle 800, 1 to 2 cm beyondits tip, and a therapeutic agent, such as a hydrogel for example canflow into path 880 across multiple levels within the paravertebralgutter 500. Also illustrated are thoracic ribs at the T1-T6 levels (R1,R2, R3, R4, R5, R6).

In some embodiments, the therapy is injected into the potential space ofthe paravertebral gutter and more preferably in some embodiments theanterior paravertebral gutter 870 (and makes flow path 881) asillustrated in FIG. 7B in order to achieve optimal rostro-caudal spreadwhile minimizing adjacent spread into the intercostal space. This may beachieved through a single injection anteriorly past the endothoracicfascia 524 to achieve multi-level paravertebral therapy to the thoracicparavertebral space or through a series of single-level injections tocover the multiple target levels. Also illustrated is the dorsal/ventralroot 830.

There is +/−1 level variability in some cases on where the stellateganglion resides, and it is a long fused ganglion so most often it isfrom C7 to T1/R1 but may sometimes be found extending between R1 and R2.It can be desirable to target the middle and/or lower stellate ganglionin some embodiments. As such, in some embodiments possible targetlocations for injection where the actual stellate ganglion location isunknown includes, for example: the bottom of R1; the middle of R1; andthe top of Rib 1 (using the rib as a landmark). On the caudal end, thefirst 4 sympathetic ganglia (T1-T4) can be covered in some embodiments.Most of the ganglia sit in between the ribs, so in some cases the agenthas to flow down to the top of the 5th rib to cover those levels. Insome embodiments, T5 is covered as well to obtain more completedenervation so the gel can travel caudally going to the next rib (R6).

FIG. 8 illustrates an embodiment of a system and method for sympatheticneuromodulation similar to that described in FIGS. 7A and 7B above, andalso including an energy delivery effector 1402, such as one, two, ormore RF electrodes for multi-segment RF ablation within a desiredanatomical target location, such as the paravertebral gutter forexample. One, two, or more hydrogels can be delivered as describedherein unidirectionally or bidirectionally. A flexible RF catheter 1400can be delivered through an introducer needle (e.g., Tuohy needle). Thegel 870 in combination with the energy delivery effector 1402 can aid inthermal spread, prevent pleural puncture, and assist in guiding thecatheter with rigidity in some embodiments. The RF catheter 1400 can beactivated to ablate one, two, or more segments, and the catheter 1400can then be rotated and deployed in a different direction, e.g., one,two or more segments caudally. In other embodiments, multiple segmentscan be ablated one at a time, from rostrally to caudally or vice versa.

Levels Targeted.

In another embodiment, the needle or catheter delivers agent to multipledermatomes or cervicothoracic levels. This can be achieved in acontiguous (stellate/T1 to T5, or T2 to T4) or non-contiguous fashion(e.g., injections at T1, T2, T3, T4 and T5 or injections at every otherlevel at T1 and T3 and T5). In one embodiment, the needle is advanced atT2 or T3 levels to deliver the therapy rostrocaudally from T1 to T4/5,in which the delivery of the therapy is discontinued upon the agentreaching T1/R1 (the first rib). In another embodiment, the needle isinserted at T4 and the agent is directed rostrally until it reaches T1to deliver therapy to T1 to T4. In another embodiment, the needle isinserted at T1 and the agent is directed caudally until it reaches T4 orT5. Generally, the sympathetic ganglia are located in between the ribswhile the chain itself (the region between the ganglia) runs over theribs, although this is not always the case. The first rib (R1) can beused as a guide for injection to T1 or the lower half of the stellateganglion. Specifically, the upper border, middle, or lower border of R1can be used as a visual marker of the transition between the T1 andinferior cervical portion of the stellate ganglion. Using the rib as amarker, the therapy can be delivered within the paravertebral gutter tothese anatomical targets. In yet another embodiment, two injections areperformed at T2 and T4 with 5 to 10 ml of therapy to fill theparavertebral gutter from T1 to T4. If coverage of the entire thoracicparavertebral space desired then preferably three injections of 5-10 mlof the formulation at T3/4, T6/7, and T8/9 can be performed in someembodiments. FIGS. 9A and 9B illustrate schematic examples of neuralanatomy and non-limiting treatment locations. In some embodiments, thesuperior 901, middle 902, and inferior cervical ganglion 903 of thesympathetic chain are spared. This target region of the T1 to T4 (or T5in FIG. 9B) paravertebral gutter is shown schematically in the regioncircumscribed by dashed line 500. Various non-limiting examples ofinjection site(s) are shown by arrows. FIG. 9B schematically illustratesmore extensive treatment depending on the desired clinical result byflowing a therapeutic agent, e.g., a neurolytic hydrogel from theinferior stellate ganglion 903 to T5. Various non-limiting examples ofinjection sites are shown by arrows A4, A5, A6.

Cervical.

The upper, middle, and inferior cervical ganglion may also be targetedwith injections of the therapy. The stellate ganglion alone or incombination with other levels is of particular interest in somediseases. For targeting the stellate, the therapy can be delivered inand beyond the paravertebral gutter from a location between R1 and R2upwards beyond the upper border of R1. Alternatively, by utilizing thevarious anterior approaches to delivering therapy to the stellateganglion using the C6 or C7 transverse process as a guide (as isroutinely used for performing stellate ganglion blocks (anesthetic)(Abdi et al 2004), the therapy can be delivered to the stellate ganglionalone or the stellate ganglion and down through the paravertebral gutterto other target levels. The transverse process of C6 is identifiedthrough palpation of the anterior part of the neck, about 3 cm lateralto midline. The palpating finger maintains transdermal contact with theprocess while controlling the left carotid artery. With the patientreclining at 20-30° and a standard long beveled 21 G needle 1.5″ needle,the needle is advanced to the bone. If desired, a 2 m length offine-bore connector or manometer tubing permits separation of the needlefor the syringe barrel, permitting finer control over the injection. Thetubing is prefilled with the injectate to avoid dead space or injectionof air. Following negative aspiration to confirm that the needle is notin the vasculature, 10-15 ml of bupivacaine is injected with repeatcheck aspirations at 3-4 ml. Patient is maintained in the semi-recumbentposition for 15 minutes. This approach may be targeted for the treatmentof, for example, tinnitus, post-traumatic stress disorder (PTSD), andhot flashes. In one embodiment, PTSD is treated with the delivery oftherapy to only the right stellate ganglion.

Lumbar.

If therapy is desired in the lumbar psoas compartment, the therapy canbe delivered in the fascial plane within the posterior aspect of thepsoas major muscle to the femoral nerve, lateral femoral cutaneousnerve, and the obturator nerve. The transverse process is the primaryguidance landmark since one third of the muscle originates from theanterior aspect of the transverse process and two-thirds originates fromthe anterolateral aspect of the vertebral body. One ml of solution mayprovide L2, L3, and L4 coverage and higher volumes may result inpostsympathectomy neuralgia that beings a couple weeks after theprocedure and may last for weeks to years.

Unilateral Vs Bilateral.

In one embodiment, the needle or catheter delivers drug to the targetneural tissue unilaterally to target the ipsilateral neural tissue. Inanother embodiment, the needle or catheter delivers drugs to the targettissue unilaterally in order to deliver the therapy to bilateral neuraltargets. For example, in one scenario, the agent is delivered on theright side of the body and spreads prevertebrally across to thecontralateral paravertebral space to target the sympathetic chainbilaterally at that level. In yet another embodiment, a procedure inwhich a needle or catheter is directed to two succinct bilaterallocations to treat bilateral neural targets is desired.

In one embodiment, a Philips iU22 ultrasound system (Philips Healthcare)with a high-frequency 3D 4D volume linear array transducer (VL13, 13 to5 MHz) is used. For a paramedian sagittal scan, the ultrasoundtransducer is positioned over the sagittal scan line at the mid-thoraciclevel with the orientation marker directed cephalad. For the transversescan, the ultrasound transducer is rotated 90 degrees to position theorientation marker laterally to obtain images between C7 to T5. Ontransverse section, the transverse process creates an acoustic shadowanteriorly obscuring the thoracic paravertebral space but the transverseprocess and pleura are readily visualized. If the injection is performedbetween 2 adjacent transverse processes away from the acoustic shadow,reflections from the superior costotransverse ligament, theparavertebral space, the parietal pleura, and the lung tissue may beidentified. The color Doppler signal of the intercostal artery can alsobe identified close to the inferior border of the transverse process. Ina multi-planar 3-D view, the thoracic paravertebral region is easier toidentify in the transverse plane. As needed, measurements of the depthof the transverse process, superior costotransverse ligament, and pleuraare taken and an angle correction for needle insertion depth can beestimated.

In another embodiment, a 180 Plus US Machine (Sonosite) with a 10-5 MHz38 mm broadband linear array transducer (depth between 5 to 7 cm) set in‘General’ imaging mode was used for preliminary ultrasound pinpointingfollowed by needle insertion. As needed, short-axis scanning can beperformed with the transducer placed medially and then moved 4 to 5 cmlaterally to pinpoint the respective paravertebral areas and vertebraland intervertebral level. The probe can also be rotated to scan the arealongitudinally (long-axis). In the short axis view, a 17-G Tuohy needle(Epi Mini Set 17 G Polymedic, Tenema) is inserted out of planeimmediately down and medial to the ultrasound probe. The Tuohy needle isadvanced point by point in increments, aiming at the paravertebral spaceafter feeling the click of the tip of the needle through the superiorcostotransverse ligament anterior to the muscle. After each advance, 0.2ml of normal saline can be injected allow for sonographic visualizationof the needle tip. Confirmation that the needle is in the paravertebralspace can be performed by injecting 1 or 2 ml of saline andsonographically observing the dilation of the paravertebral space. Oncethe space is identified, the needle is disconnected from the normalsaline syringe/barrel and after a negative blood and air aspirationtest, the formulation is delivered. As required, the air aspiration testmay also serve to remove the saline from the needle lumen in preparationfor delivery of the therapy. In an alternative embodiment, a soft-tipped19-G polyethylene catheter can be inserted 2-3 cm beyond the tip of theneedle, the needle removed, and the therapy delivered from the catheter.In yet another embodiment, a slightly oblique ultrasound scan isperformed using a curved array transducer to provide visualization ofthe transverse process, pleura and costotransverse ligament. After aninline approach with an 16 G-18 G Tuohy needle approximately 2 to 3 cmlateral from midline, 10 ml of normal saline is injected to confirm theposition of the needle tip by distension of the space under ultrasoundprior to delivering the therapy through the same lumen. Color Dopplerimaging may be used to help determine the location of the injectate.Under ultrasound guidance, a lateral subcostal approach at the angle ofthe rib is taken and ultrasound is used to identify the rib, the spacebetween the inner and internal intercostal muscles, and the pleura.Injectate will travel from this location back to the paravertebralgutter where it can ascend or descend several dermatomes.

In one embodiment, the hydrogel is injected beyond the costotransverseligament. In yet another embodiment, it is injected 1 cm from thepleura.

Lumbar.

Ultrasound guidance can similarly be used to access the lumbar plexususing either the transverse or longitudinal axes. In some embodiments,the ultrasound transducer is placed 4 to 5 cm lateral to the lumbarspinous process at a depth of 11-12 cm, frequency of 4 to 8 MHz to. Thetransverse process of L3-L4 is identified, and the transducer isdirected medially to assume a transverse oblique orientation. The psoasmuscle, just deep to the transverse process, can be visualized throughthe acoustic window between the two adjacent transverse processes. Thearticular process of the facet joint, the deeper inferior vena cava onthe right or aorta on the left, and the intervertebral foramen can bevisualized with this approach. The needle is guided to the posteriorpart of the psoas muscle where the roots of the lumbar plexus arelocated. Other techniques are detailed, for example, on the web pagehttp://www.nysora.com/techniques/neuraxial-and-perineuraxial-techniques/landmark-based/3282-lumbar-plexus-block.html.

Stellate.

There are several approaches to the stellate ganglion as described, forexample, elsewhere herein.

Ultrasound.

In some embodiments, the injections are performed under real-timeultrasound, MRI-, CT- or fluoroscopic guidance with lower rates ofcomplications. In the preferred embodiment, the paravertebral space isaccessed under ultrasound guidance. The transcutaneous procedure may beperformed through either a transverse or oblique paramedian (OPM) orsagittal approach with either in-plane or out-of-plane needle entry(Krediet et al 2015). High resolution ultrasonography using a highfrequency linear array probe (5 to 10 MHz or 8-15 MHz) can improve theefficacy and safety of the procedure. If the thoracic levels targetedare very high because of the trapezius and rhomboid muscles or lowbecause of the erector spinae muscles, a different probe may beselected. The patient can either be placed in a seated, lateraldecubitus or prone position. Prior to the procedure, the spinousprocesses and injection sites can be drawn on the patient. Similarly,the rostral and caudal extent that the therapy will be delivered can beexplored with ultrasound prior to the procedure by moving the probelongitudinally. A 17 or 18 gauge Tuohy needle can be desirable forvisualization and stability as well as the ability to inject the gel.

Tracking Spread.

In the aforementioned approaches, the rostrocaudal spread of the therapycan be tracked with ultrasound. In one embodiment, the rostral spread oftherapy can be followed with the ultrasound probe longitudinally(long-axis). The therapy can be preferably echogenic such that itstravel can be tracked. In another embodiment, the ultrasound probe ismoved to the furthest edge of the target level. In the treatment of theupper thoracic sympathetic procedures, the ultrasound probe can beplaced at T1, the stellate ganglion, or T2, to visualize the mostrostral spread of the therapy and discontinue the delivery of thetherapy to the paravertebral space. Alternatively, if the therapy isdelivered to the paravertebral space from the stellate ganglion/T1, theultrasound probe can be placed at T4 or T5 to visualize the most caudalspread and then discontinue the injection of the therapy once the targethas been reached.

Blank Hydrogel.

In one embodiment, the top boundary of the first rib is first injectedwith blank hydrogel, approximately 2 to 5 ml, to surround the inferiorcervical ganglion or upper half of the inferior cervical ganglion andprovide a physical barrier to the spread of neuromodulatory agent orneuromodulatory-agent loaded hydrogel, to the inferior cervical ganglionand the numerous other structures in the lower cervical region. This maybe performed as a separate procedure or it may be performed contiguouswith the administration of the neuromodulatory agent-loaded hydrogel. Inone embodiment, the device that delivers the therapy has a valve at thedistal end of the barrel, proximal to the needle that permits blankhydrogel to be delivered first followed by neurolytic agent-loadedhydrogel second. In another embodiment, the Tuohy needle is divided intotwo channels inside the needle with two non-contacting circular sideports on either side of the needle. In this embodiment, one exit portmay be through the needle bevel and the other a side port on theopposite of the needle from the bevel. Alternatively, the needle may nowpermit exit of the therapy from the bevel, but from two ports on eitherside of the needle, each connected with the internal channels, to permitflow of blank hydrogel rostrally and neurolytic-agent loaded hydrogelcaudally either serially (blank first) or together. Alternatively, anatraumatic blunt catheter can be advanced approximately 1 cm from theTuohy needle to deliver the therapy from a side port or a two-channelcatheter can be advanced approximately 1 cm from the Tuohy needle todeliver a blank hydrogel in one direction and the neurolyticagent-loaded hydrogel in the opposite direction. Alternatively, acatheter can be inserted to the paravertebral space over the trip of theneedle and advanced by 1 cm before the needle is removed. In still otherembodiments, a balloon or curtain or other device can be expanded from adelivery port on the needle to prevent backflow of gel to non-targetlevels. Alternatively, a catheter with a soft atraumatic tip that has asteering handle and locking mechanism can be advanced to preferentiallydeliver the therapy rostrally or caudally by preferentially directingthe tip of the device rostrally or caudally. The aforementioned devicesmay contain another port to allow for delivery of additional anesthesiaas necessary without having to move the device.

Protection from Pleural Puncture.

The Tuohy needle bevel can be shortened as desired to render the tipless traumatic. In some embodiments, the gel is delivered directly fromthe Tuohy needle. In other embodiments the gel is delivered from acatheter that is extended between 1 and 2 cm from the tip of the Tuohyneedle. This provides a mechanism to direct the flow of the therapyrostrally or caudally through the use of an atraumatic steerable tip.Preferably the tip is visible under ultrasound, particularly as it isadvanced away from the acoustic shadow.

Ports for Delivering Therapy.

Thermosensitive, shear-thinning, or other hydrogels can be injectedthrough a single lumen or port, or multiple lumens. Cross-linkedhydrogels, which typically contain two or more components, can be mixedin various settings including 1) out of the patient (pre-mixing), priorto delivery, 2) within the delivery device but still outside of thepatient, 3) within the delivery device, within the patient, and 4) atthe distal tip of the delivery device, inside the patient. In the caseof the mixing being required near the tip of the catheter, a multi lumencatheter with a transition zone that permits turbulent flow might allowfor more flexibility to mix the agent more proximally to where it isinjected in some embodiments. The transition time from a solution to agel can be controlled by relative mixing the agents and their relativeproportions. In one embodiment, the extent of the caudal spread isdetermined by what levels the gel travels to relative to the T1 gangliaand the 1^(st) rib. In another embodiment, the agent spreads down fromthe R1 rib/thoracic ganglia to the R4 or R5 (rib) level. In anotherembodiment a balloon is inflated of a compliant sheet of material isdeployed to prevent spread in the opposite direction from the needletip.

Identifying the Correct Anatomical Location.

The desired spread of the neuromodulatory agent can in some embodimentsbe in a longitudinal spreading pattern instead of intercostal (IC),cloud-like (CL) spread or a combination thereof. In one embodiment, thespreading pattern of the neuromodulatory agent or neuromodulatoryagent/gel can be better controlled by placing the needle with theguidance of a nerve stimulator, in the more ventral part of the thoracicparavertebral space, anterior to the endothoracic fascia, to achievemulti-segmental longitudinal spread. This helps to prevent non-targetspread and also reduces the volume of neuromodulatory agent that needsto be delivered to achieve spread to the target levels of thesympathetic chain. The thin endothoracic fascia is the deep investingfascia of the thorax and attaches to the ribs and medially to themid-point of the vertebral body, dividing the paravertebral space intoan anterior and posterior compartment. Clinical studies havedemonstrated that, using a dorsal paravertebral approach, the needleinitially enters the dorsal part of the TPGS which results in musclecontractions at 2.5 mA and then, as the needle position is advanced tothe ventral portion of the TPGS in close proximity to the nerve, anappropriate muscle response of 0.5 mA is observed.

In one embodiment, a single puncture is performed at the desired level(between T2 and T8) region using a nerve stimulator guided technique. Atthe T3 location, the costotransverse ligament is punctured using a 21gauge unipolar insulated needle with a conductive atraumatic shortbeveled tip (10 cm long, Stimuplex, B. Braun) and a nerve stimulator(initial stimulating current at 2.5 mA, 1 Hz, 9V) is advanced until anappropriate intercostal (upper thoracic) or abdominal muscle (lowerthoracic) response is visualized. The needle is then further advancedanteriorly until the appropriate muscle response can be achieved withstimulation at a current less than 0.5 mA or less (1 Hz, 9 V) and theinjection is performed at this location. In this embodiment, the needletip is close to but not in the sympathetic chain. Approximately one to15 ml of the neuromodulatory formulation, such as one to 10 ml ofneuromodulatory are delivered and can spread approximately one to 6levels longitudinally, or more preferably one to 4 or 5 levels.

Methods related to the use of robotics for both the diagnostic andtherapeutic, or combined modalities, are also described. Robotic systemscan be used to deliver the therapy stereotactically to the paravertebralgutter and then integrated diagnostic electrodes can be used to monitorthe neural response to therapy whether through a percutaneous orendovascular approach. These robotic systems may provide advancedneedle/catheter control including force sensing, temperature sensing,rotation, advancing and withdrawal, and tip curve control, balloonexpansion. For example, the Stereotaxis system (Niobe MagneticNavigation System) which has been used to treat hypertension via renaldenervation might also be useful for this application. The system caninclude an irrigated magnetic catheter and an advanced electroanatomicmapping system allowing for advanced mapping and navigation allowing forless contrast and radiation. Alternatively, a robotically controlledsteerable catheter like the one developed by Hansen Medical (Magellan orSensei Robotic control systems) could be used to facilitate accuratenavigation and delivery of the different ablative modalities (RF,Cryotherapy, neuromodulatory agents, etc.) to the paravertebral gutter.In another embodiment, a percutaneous needle arm with a subcutaneouselectrode placed and held in the paraspinal musculature to record thesympathetic activities prior to, during, and after therapy withoutconcern for procedural needle or catheter inadvertently moving duringthe procedure due to operator error, such as with the Intuitive DaVinci. In another embodiment entry into the appropriate location withinthe paravertebral gutter can be conveyed with a signal on the handpiece,such as a green In another embodiment, integrated ultrasound guidancesystem provides feedback on the needle tip location (e.g. shown in redsuperimposed on ultrasound image) as well as the trajectory of theneedled tip (dotted green line, a projection of path going forward). Insome embodiments, the robotic arm can include a needle attachment for aposterior approach to the spine allowing the use of more sensitive andquantitative force-sensing at the catheter tip or tool tip and or directvisualization with miniature cameras to assure that vessels are notdamaged

In another embodiment, a subcutaneous electrode placed in the paraspinalmusculature records the sympathetic activities prior to, during, andafter therapy. In another embodiment entry into the appropriate locationwithin the paravertebral gutter can be conveyed with a signal on thehandpiece, such as a green In another embodiment, the ultrasoundguidance system provides feedback on the needle tip location (e.g. shownin red superimposed on ultrasound image) as well as the trajectory ofthe needled tip (dotted green line, a projection of path going forward).In another embodiment, this procedure can be performed with an roboticarm, such as the Intuitive Da Vinci with a needle attachment for aposterior approach to the spine allowing the use of more sensitive andquantitative force-sensing at the catheter tip or tool tip and or directvisualization with miniature cameras to assure that vessels are notdamaged

Monitoring Sympathetic Tone During and after the Procedure.

Classical methods to determine the effectiveness of sympathetic blockare to measure changes in skin temperature, heart rate, and/or heartrate variability. Microneurography may also be used to measure changesin peripheral sympathetic nerve activity, for example in muscle. At thestellate level, the most common sign of the effectiveness of the blockis Homer's syndrome (unilateral miosis, ptosis, and anhidrosis),however, since the fibers to the head and neck to not supply the thorax,the presence of Homer's syndrome is not indicative of cardiopulmonaryblock or denervation. As a result, there is a need for more specificmethods to monitor cardiac or pulmonary sympathetic tone to determinethe efficacy of a neuromodulatory therapy intraprocedurally. Moreover,the ability to deliver the neuromodulatory therapy at one level withinthe paravertebral gutter and be able to confirm successful delivery ofthe therapy to another level of the paravertebral gutter through themodulation of sympathetic nerve activity at another level can bedesirable. In another embodiment, fusion imaging, with real-time3-dimensional visualization and navigation tools can be utilized toguide the procedure. By using the spinous processes to register theultrasound images with a 3-D reconstruction of 2-D CT or MRI images,structures that could otherwise not be seen with ultrasound arerevealed.

Subcutaneous monitoring can provide a convenient and minimally invasiveapproach to monitoring sympathetic ganglia nerve firing. In oneembodiment, such as when a transcutaneous approach to delivering thetherapy will be undertaken, electrodes are placed subcutaneously tomonitor the subcutaneous sympathetic nerve activity at the level(dermatome) that is directly innervated by the sympathetic nerves towhich the therapy is administered. Alternately, the subcutaneous nervesarising from an adjacent or more distal level from where the therapy isadministered, can be monitored. Specifically, two pairs of bipolarelectrodes are placed at an interelectrode distance of 4 cm in thesubcutaneous tissue superficial to the third intercostal space.Ipsilateral subcutaneous sympathetic nerve activity in the upper thoraxarises from the dorsal cutaneous branch which supplies fibers to theramus cutaneous lateralis and a deeper branch to the paraspinal muscles.In particular, Robinson et al (2015) have demonstrated in dogs that theparaspinal subcutaneous sympathetic nerve firing patterns correlate wellwith the activity of the cardiac visceral sympathetic nerve firingpatterns. With the appropriate signal filtration and processing, asdescribed in Robinson et al (2015), recordings of subcutaneoussympathetic nerve activity (SCNA) (that correlate with cardiac(stellate) sympathetic nerve activity (SGNA)) are made.

In some embodiments, the spontaneous sympathetic nerve activity can berecorded subcutaneously at baseline prior to the delivery of thetherapy, during the therapy and after the therapy. In one furtherembodiment, successful paravertebral spread of the hydrogel up to the T1(stellate ganglia) after the injection of material into theparavertebral gutter between the third and fourth ribs can be confirmedby monitoring the subcutaneous sympathetic nerves in the dermatomesupplied by the stellate/T1 ganglion. In other embodiments, it can berecorded continuously, as described in 2006/0004413, which is herebyincorporated herein by reference in its entirety. If the spontaneousactivity is not enough, the patient can receive an IV injection of aneurostimulatory agent, such as adenosine or apamin for example.Successful neurolytic ablation of the stellate ganglion would theneliminate or reduce the activity triggered by the administration of theneurostimulatory agent.

Alternatively, an electrode catheter or electrode needle (StimuplexUltra, Braun) can be placed in the paravertebral gutter and thesympathetic ganglion can be stimulated and or locally during theprocedure. In one embodiment, the catheter or needle delivering thetherapy can stimulate and or record the sympathetic nerve activity.Alternatively, the sympathetic nerve activity of a distal ganglion canbe recorded with an electrode placed percutaneously in the paravertebralgutter, such an electrode placed at the lower border of the 1^(st) ribto measure the T1 (stellate) ganglion activity. This provides additionalconfirmation beyond ultrasound that the appropriate spread of theneuromodulatory agent in a hydrogel has occurred from the level fromwhich it was injected to reach the distal and furthest target that thetherapy is targeted, in this example, T1. In yet another embodiment,cervical sympathetic activity can be monitored through a subcutaneousand or direct paravertebral approach to confirm the absence of a changein sympathetic activity in non-target cervical level or lower thoraciclevels, for example.

As with transcutaneous approaches to monitoring procedural efficacy,endovascular monitoring approaches are also desired. When the therapywill be administered through an endovascular, particularly intravenousapproach, a variety of diagnostic and stimulatory electrophysiologycatheters can be employed at various locations within the vasculature toassess the effectiveness of the therapy and the appropriate spread ofthe agent to the desired targets within the paravertebral gutter. In oneembodiment, an endovascular catheter with a stimulating electrode isplaced substantially adjacent to the sympathetic chain, such as in anintercostal artery or vein, the azygous vein (or hemiazygous/accessoryhemiazygous), the subclavian artery, or the costocervical trunk. Theelectrodes in this embodiment can in some cases be preferably located onthe same catheter that is delivering the therapy transvascularly to theparavertebral gutter. The diagnostic electrodes can be used to locatethe sympathetic chain, such as where the vessel crosses the sympatheticchain (e.g. superior intercostal vein) or where the vessel is in closeproximity to the sympathetic chain (subclavian artery, one of theazygous or intercostal veins). After determining the chain location orthe direction of the chain, the catheter can deliver the therapy to theparavertebral gutter in and around the sympathetic chain. In thismanner, the sympathetic chain allows identification of the paravertebralgutter. Alternatively, the diagnostic electrodes can be used to recordthe spontaneous firing of the sympathetic chain discretely orcontinuously during the procedure to confirm the effectiveness of thetherapy at that level. Other embodiments permit diagnostic cathetermonitoring of adjacent levels to confirm the spread of the therapyrostrally or caudally. In one embodiment, the therapy is delivered fromthe superior intercostal artery into the paravertebral gutter and adiagnostic catheter is placed in the 4^(th) intercostal vein to recordthe activity of the sympathetic ganglia/chain there.

Alternatively or in addition to the above, diagnostic EP catheters canbe placed endovascularly to monitor the activity of the post-ganglionicsympathetic fibers as they course to the heart and lungs and greatvessels. For example, diagnostic electrophysiology catheters can beplaced in the coronary sinus, the high right atrium, the subclavianartery or the right ventricular apex, to monitor cardiac sympatheticnerve activity. Diagnostic catheters can be placed in the pulmonaryarteries, pulmonary trunk and bifurcation, lower curvature of the aorticarch, or the aorta to measure cardiopulmonary sympathetic activity.Diagnostic catheters can be placed in the bronchial and pulmonaryvessels as they enter the lung hilum to monitor pulmonary sympatheticactivity. In these endovascular embodiments, the parasympathetic andsomatic nerve activity may also be monitored, particularly since thevagus and the fibers coming off of the vagus often travel with thesympathetic nerves. In one example, left cardiac sympathetic nervefiring can be recorded in the left subclavian artery by locating theelectrodes substantially adjacent to the ansae subclaviae (AS). Byrotating, advancing, or withdrawing the catheter in the subclavianartery the AS site can be identified by measuring a change in arterialpressure increase, as described in Zarse et al 2005. Once located, thecatheter can be stabilized in this location to provide ongoingmeasurement of sympathetic nerve activity and or to provide localtransvascular stimulation of these nerves, as needed.

In order to assess the cardiopulmonary response to the therapy,hemodynamic measurements using a Swan-Ganz catheter to record pulmonaryartery pressure and determine cardiac output, heart rate, totalperipheral resistance, sinus rate and sinus cycle length, and rates ofLV systolic pressure increase can be made. Electrophysiologicmeasurements including RR, PR, QRS-QT, QTc intervals can be measured aswell as local conduction velocity, as detailed in (Zarse et al 2005).These measurements can made at baseline, pre-procedurally, andpost-procedurally to assess changes in cardiopulmonary sympathetic nerveactivity. In this manner, the successful delivery of the therapy to theparavertebral gutter can be assessed.

Guidewires with electromechanical sensing tips may be suitable devicesfor monitoring the activity of the cardiopulmonary sympathetic nerves atthe aforementioned locations and assessing the success of the procedureas described in U.S. Pub. Nos. 2016/0029960 and 2015/0224326, which arehereby incorporated herein by reference in their entireties.

Another approach, particularly for the development of devices to treatcardiac arrhythmias, the therapy can be performed in conjunction with adiagnostic EP study, as known in the art. During the these studies,electrodes are placed in the high right atrium near the sinus node, thearea of the His bundle, the coronary sinus that lies in the posterioratrioventricular groove and near the left atrium and ventricle and inthe right ventricle. Carotid sinus massage and pharmacologicadministration of sympathetic and parasympathetic agonists andantagonists (infusions of atropine, isoproterenol, epinephrine, betablockers) can be used to monitor changes in autonomic balance betweenthe sympathetic and parasympathetic systems before, during, and afterthe procedure. Also, programmed electrical stimulation, targeted at thesinus node, AV node, His-Purkinje system and ventricular myocardium canalso be used to assess autonomic function. These procedures may also beused to guide the additional administration of the therapy to adjacentlevels. In one embodiment, cardiac sympathetic innervation is notsignificantly reduced after delivery of the therapy to, for example, tothe paravertebral gutter from the bottom of the first rib to the bottomof the 5^(th) rib. In this embodiment, assuming successful proceduralplacement of the neuromodulatory hydrogel, additional neuromodulatoryhydrogel may additionally be delivered to the upper half of the stellateganglion, specifically the inferior cervical ganglion, such as throughan anterior percutaneous image-guided procedure targeting C6/C7.

Repeat Procedures.

As necessary, the agent or therapy may be delivered on successivetreatment days. In one embodiment, an anesthetic is delivered to atarget site(s) to confirm safety and/or efficacy and the non-reversibletherapy is then delivered on the same day or within 30-days of the trialanesthetic procedure. In another embodiment, the therapy is delivered atregular intervals in order to maximize efficacy. For example, thetherapy can be delivered at 0, 30, and 60 days at the same levels oradjacent levels.

Combination Therapy.

The therapy may be delivered in combination with acute or chronic drugtherapy, any other therapeutic denervation therapy such as renaldenervation, adrenal denervation, pulmonary trunk or bifurcationdenervation, pulmonary artery denervation, carotid body denervation,baroreceptor denervation, and tracheal or bronchial denervation,coronary artery bypass graft, atrial or ventricular arrhythmia ablation,or procedures to produce complimentary or synergistic effects in thetreatment of chronic diseases, particularly since there are manycomorbidities associated with these diseases.

Direct needle injection into the sympathetic chain/ganglia. Directinjection into nerves is often avoided in some embodiments because ofconcerns of damage to the nerves. However, in some embodiments, targeteddelivery of a neuroablative agent within the sympathetic chain andganglia itself is possible. In one embodiment, a needle enters thesympathetic chain either directly or indirectly and a volume, e.g., 5 mlof the therapy mixed with contrast agent is injected into the chainitself. The agent may travel within the sympathetic chain and theepineural sheath itself rostral and caudal to the injection site. Thereare examples of diffusion of 15 and 30 ml of dye within the tibial nervebetween approximately 14 and 17 cm, respectively.

Endovascular Approaches.

With any of these approaches, in some embodiments the goal ofadministering therapy is to disrupt the internal and/or external reflexarcs within the lung, heart and the surrounding vessels to achieve abeneficial therapeutic effect. This can be achieved by disrupting nervefibers that innervate an anatomical target, such as the lung directly orthat innervate targets that also indirectly modulate cardiopulmonaryfunction such as the nerves that afferent/efferent nerves that innervatethe carotid sinus and baroreceptors or carotid body, aortic archbaroreceptors, pulmonary trunk and pulmonary artery baroreceptors,pulmonary and bronchial artery innervation.

Unilateral vs Bilateral. The therapy can be delivered either from anendovascular approach or a percutaneous approach aimed at gaining accessto the region containing the targeted neural structures. In oneembodiment the therapy is delivered unilaterally to either the right orleft paravertebral gutter. In another embodiment, the therapy isdelivered bilaterally, to both the right and left paravertebral gutter.In another embodiment the therapy is delivered to the anterior orposterior rami unilaterally or bilaterally. In these instances, one,two, or more spinal levels or dermatomes are treated. In someembodiments, the target region for neuromodulation is the nervescontained within and crossing through the thoracic paravertebral space(TPVS) on their way directly or indirectly to the heart, lungs, aorta,esophagus or other organs or vessels.

The targeted neural structures may be coursing through a potential space(TPGS) or coursing over or along a vessel. The sympathetic chain, forinstance, travels largely parallel to the azygous/hemiazygous veinsuntil it reaches upper four levels of the sympathetic chain. On theright side, the second, third and fourth posterior intercostal veinsgather medially to form the superior intercostal vein which connects tothe azygous vein on the right side. On the left side, these veinsconnect to the hemiazygous or accessory hemiazygous vein. For the mostpart, the sympathetic chain crosses anteriorly to these vessels.

Anatomic Landmarks on Fluoroscopy.

The head of the ribs can be used as a guide for the location of thesympathetic chain and thus the paravertebral gutter under fluoroscopy.FIG. 10A illustrates one embodiment of possible selected upper thoracicanatomy, including thoracic ribs R1, R2, R3, R4, R5, and the sympatheticchain 701 coursing anterior to the ribs. Also illustrated is thesuperior intercostal vein 702 which can course under the sympatheticchain 701 and other intercostal veins, e.g., 703. For example, T1, T2,and T3 are approximately 4, 6, and 6.4 mm from the medial margin of therib head. Using this as a guide, the delivery of the therapy into theparavertebral gutter can be straightforward. However, given thevariability in the vein sizes at the upper thoracic levels as well asbetween the right and the left side, as well as the variability in thefirst 4 levels of the sympathetic chain 701, the device design can insome embodiments be versatile and flexible for different sized vesselsand can permit the delivery if the vein 702 is running parallel to oracross the paravertebral gutter. There is a unique relationship thatexists between the ribs R and the sympathetic chain 701, as illustratedin FIG. 10B. In some embodiments, the location of the sympathetic chain701 can be utilized as a marker for the paravertebral gutter, because:(1) The ribs R are in a known location under fluoro; (2) the sympatheticchain 701 very predictably travels in parallel to the spine effectivelyorthogonally to the ribs R; (3) the sympathetic chain 701 is bydefinition in the paravertebral gutter; and (4) if the distance of thesympathetic chain 701 from the gutter is known, one can likelysuccessfully inject within the paravertebral gutter. The tables belowinclude some embodiments of distances from the medial margin of rib headto the medial margin of sympathetic chain shown as distance D in FIG.10B (mean±SD).

TABLE 3 Distance from medial margin of rib head to the medial margin ofsympathetic chain (mean ± SD) (Lee et al 2011) Level of vertebrae Rightside Left side T1 4.1 ± 0.8 4.4 ± 1.1 T2 6.1 ± 1.3 5.7 ± 1.1 T3 6.6 ±1.1 6.1 ± 1.1 Width of sympathetic chain± T1 5.7 ± 1.6 6.6 ± 1.7 T2 4.1± 1.0 4.2 ± 0.7 T3 3.0 ± 1.2 3.4 ± 0.7

In this way, one can be freed from trying to understand the particularsof the venous anatomy relative to the chain or the gutter and can focuson the relationship between the rib and the catheter. This can beeffective, for example, as a particular solution for R2, R3, and R4 andfurther rostral. It may or may not be as effective for R1, as the vesselmay be running parallel to chain).

Some embodiments can include the following steps: (1) insert thecatheter at (R2, R3, R4) intercostal or superior intercostal vein; (2)the fiducials are located at a fixed distance relative to one another,and one is directly aligned with where the needle exits. For example,one fiducial is at tip and the other fiducial is at the level where theneedle is injected and then another fiducial on the catheter (backtowards handle) is 7.5 mm.

In some embodiments, a fiducial can be in a shape such that it is clearwhich way it is facing. When, for example, an L shaped fiducial is inthe correct location, it can be read under fluoro, when it is in theincorrect location it looks like an upside down L. Other shapes can beused. This can assure that the needle is pointing ventrally.

Bone. Either transcutaneous or endovascular. In one embodiment, a safetydevice can be designed so that the therapy cannot be injected unless itis in contact with bone. In this way, the catheter tip, or the bluntneedle tip are advanced and there is a mechanical probe on the tip thatmakes contact with the bone. When the probe tip is appropriately pushed,an internal valve inside the lumen of the catheter/needle is pushed suchthat the lumen lines up with the opening on the side of the catheter. Inone embodiment, the opening is directed rostrally, in another embodimentit is directed caudally. In yet another embodiment, it is directedlaterally. In another embodiment, communication from two channels islined up with two openings on either side of the catheter when the probeis appropriately pushed. In one embodiment, the mechanism of actuationis spring-loaded, in another embodiment it is a button that requiresless force to actuate. In another embodiment, the sensor is an impedancesensor, detecting a difference in impedance between the bone andnon-bone. In another embodiment, the sensor delivers an electricalsignal and measures the threshold for stimulation before this istranslated into a mechanical opening. By offsetting the opening off ofthe tip of the catheter, delivery of the therapy is assured within theparavertebral gutter. When the probe tip is not engaged or activated,the valve or opening to deliver the agent is closed (safety valve) andit acts as a safety mechanism to prevent injection of neurolytic agentin the wrong location. In one embodiment, the device itself has a closedloop system to stimulate and record the electrical or electromyographicsignals (nerve, muscle, respectively), first to confirm the correctlocation and then, during and after the procedure to confirm that thetherapy was delivered.

Endovascular. In one embodiment, the intercostal vein or superior(supreme) intercostal vein are pushed up against the inferior edge ofthe rib and the agent injected here in and around the rib head.

Transcutaneous/Percutaenous. In one embodiment, the catheter or needlemakes contact with the vertebral body and agent is injected from hereinto the paravertebral gutter.

In some embodiments, the paravertebral space can be accessed on thevenous side through an endovascular access approach via a suitable veinsuch as the femoral vein, a subclavian vein, or internal jugular vein onthe right or left side. Therapy can be delivered, for example, from aproximal location within the internal jugular, the supreme/superiorintercostal vein, the azygos vein, intercostal vein(s), azygous arch,the venous communication between the hemiazygous and azygos veins, thehemiazygous vein, the accessory hemiazygous vein, or the vena cava. Theparavertebral space can be accessed on the arterial side through anendovascular access approach via a suitable artery such as the femoralartery, subclavian artery, brachial artery or radial artery. The therapycan then be delivered from the aorta, the aortic arch, the pulmonaryarteries, the bronchial arteries, the subclavian artery, thecostocervical trunk and/or the intercostal arteries. The followingdescription describes some embodiments of different access routes inmore detail. Vascular access may be preferred in some embodiments overparavertebral access as it may provide a more straightforward and safemethod to deliver the therapy into the anterior paravertebral gutter.

Venous Access.

Right Side.

From a femoral vein, a catheter can be inserted up the inferior venacava to the superior vena cava from where it can travel across the archof the azygos vein to access the right thoracic paravertebral space.

On the right side, the second, third, and fourth intercostal veins draininto the azygous vein located on the medial side of the fourth or fifthrib head. A large intercostal vein is present in approximately 40% atthe third and 70% at the fourth intercostal space (Haam) but themajority of the veins at the third intercostal space are medium orsmall. The majority of these veins take a posterior pathway relative tothe sympathetic chain but between 15-28% take a more anterior course.These intercostal veins course through the paravertebral gutter; eitherthe sympathetic chain or the distance from the azygous vein or bonylandmarks (vertebral body, rib head) can be used as landmarks todetermine the site of administration of therapy to assure delivery intothe paravertebral space.

At T4/T5 and below, the azygous vein runs more or less parallel to thesympathetic chain. At these mid- to lower-thoracic levels, the therapycan then be delivered directly from the azygous vein itself towards theparavertebral space containing the sympathetic chain and rami. Althoughthe azygous vein is just outside of the paravertebral gutter, byutilizing the ease of movement of the vessel within the fasciasurrounding the vein, the catheter can assume a biased configurationagainst the left/lateral wall of the azygous vein to approximate theparavertebral space. The catheter can then advance a needle at a 0 to 90degree angle into the space, more preferably a 30 or 45 degree angle todeliver the therapy into the paravertebral space. In one embodiment, theneedle is inserted posteriorly, posteriolaterally, or laterally to avoidinadvertent pleural puncture. The two key structures to avoid are thepleura and the intervertebral foramen. If the injections are lateral,the likelihood of delivering agent into the intervertebral foramen islow. Fiducials can be placed on the catheter and the handle to make surethat the orientation of the needle and catheter is correct. Furthermore,by utilizing a needle with a curved trajectory, it is possible to‘catch’ the thin wall of the vein and advance a needle across it.Alternatively, an expandable highly compliant conformable balloon can beexpanded within the space causing a balloon to unfurl and deliver aneedle through the vascular wall such as the Mercator Bullfrog catheteras described in U.S. Pat. No. 8,708,995, which is hereby incorporated byreference in its entirety. Alternatively, devices developed forinjecting cells into cardiac tissue can be adapted for delivery of thetherapy to the paravertebral gutter, including the TransvascularTransAccess Delivery System, Stiletto, Myostar, and Myocath devices,C-Cath devices. In one embodiment, the catheter can be advanced andpressed against the bone of the rib or the vertebral body, so thetherapy can be injected safely without concern for the pleura. Contrastagent can be administered to ensure correct delivery into the anteriorparavertebral space as well as the appropriate rostrocaudal spread. Inaddition, because a relative large volume is being injected through aneedle (e.g. 5-10 ml) as opposed to 0.1-1 cc of fluid, the device mayneed to be secure so that the needle does not inadvertently slip backinto the vasculature and inject gel into the bloodstream and/or tear thevein. In some embodiments, the systems and methods can include anindicia of needle trajectory on or operably connected to the deliverydevice, such as described for example in U.S. Pat. No. 6,746,464 toMakower, hereby incorporated by reference in its entirety.

Alternatively, the catheter can be advanced and inserted from theazygous vein into the superior intercostal vein. (In some instances, thesupreme intercostal vein is accessed off of the right brachiocephalicvein (right innominate vein) or subclavian in which case a subclavianvein access approach may be selected.) At this right R1 level, thesympathetic trunk is immediately adjacent to the supreme intercostalvein to the first rib, as verified under fluoroscopy. The catheter canbe configured to bias medially along the rib to deliver the agent intothe paravertebral gutter and the needle can be advanced in theposteromedial direction to deliver the agent safely into the anteriorparavertebral gutter. In this approach the curved needle enters and thendirects the flow of drug caudally, delivering the therapy from T1 downto T4 or T5. Thus the therapy is delivered from the supreme intercostalvein will flow to multiple paravertebral levels. Typically a volume of 5to 10 ml of agent will be delivered. In some instances, lateraldeflection of the supreme intercostal vein will be required to accessthe paravertebral gutter. This can be accomplished via a steerablecatheter and/or guidewire in some embodiments.

In another embodiment, multiple overlapping injections are made withsmaller volumes of agent to the paravertebral space. In this approach, asmaller volume is delivered at the 1^(st) rib (between 2 to 5 ml) fromthe supreme intercostal artery and then the catheter is advanced untilit is adjacent to the 2^(nd), 3^(rd), and 4^(th) rib (R2, R3, R4) eitheroff of the supreme intercostal artery or from second through the third(or fourth) intercostal veins. If additional levels need to be treated,the catheter can then be returned to the azygous and advanced directlyto each of the fourth, fifth, and/or sixth intercostal veins. (Thefourth intercostal vein may come off either the superior intercostalvein or the azygos vein in some cases) In one embodiment, therapy isdelivered at each of the desired intercostal levels on each side, usingthe ribs as a visual guide. The use of a contrast-loaded gel can guidethe physician how far apart to make the injections and what volume todeliver.

In yet another embodiment, the catheter can be directed within thevenous system to deliver therapy from one location to multiple adjacentlevels: in which the location is the 1) the azygos vein, preferably atthe level of the third or fourth rib, 2) the second intercostal vein, 3)the third intercostal vein, 4) the fourth intercostal vein, or the 5)fifth intercostal vein and an injectable neuromodulation agent can bedelivered to reach multiple contiguous thoracic levels through thecontinuity provided by the paravertebral space. The agent or therapy canthen be delivered rostrocaudally, rostrally, or caudally to multiplelevels to ablate the nerves in the paravertebral gutter. In someembodiments, the agent can travel around the vertebra to reach the bothparavertebral spaces. If therapy is delivered from the azygous veindirectly, it can be preferable in some embodiments to deliver therapybetween the branches of the intercostal arteries towards the sympatheticchain. If the therapy is delivered from the intercostal vessels, in someembodiments the therapy is injected as the catheter is biased toward theintercostal vessel branch, and a needle extended from the tip of thecatheter into and through the venous wall. In some embodiments, theneedle is a curved needle so that it can ‘catch’ the venous tissue onits trajectory.

In another embodiment the device includes a catheter with a steerableand/or curvable needle that can be advanced directly out of the tip ofthe catheter to catch the rostral venous wall as the intercostal veinarches off of the parent vessel. The needle punctures the vessel at therostral side of the vein so that neither the sympathetic chain or thepleura are punctured. The needle can have a preset curve (e.g., made ofnitinol or another shape memory material) or can be deflectable throughan angular range (e.g., via one or more pullwires connected proximallyto a control that can be actuated by an operator).

The therapy can also be directed towards the fibers that and run acrosson either side of the azygous vein on their way to the pulmonary hilum.In this manner, fibers traveling from the cervical and thoracic chainthat travel across or around the azygos vein on the right side can betargeted. In some cases, the azygous curves over and grooves the rightlung before entering the superior vena cava just before it enters theheart and is known as the azygous lobe of the lung or the azygous arch.In one embodiment, therapy is directed from the curve of the azygoustowards the nerves that cross the azygous or that are in proximity tothe azygous that directly innervate the lung, such as the anteriorand/or posterior pulmonary plexi or nerves that innervate the heart,such as the superficial and deep cardiac plexus. Unlike other therapiesdirected at denervation, circumferential ablation of these vessels maynot be necessary because the fibers to the heart and lung are crossingover the vessel as opposed to coursing along it. In some embodiments,two linear ablation RF lines are made on either side of the azygous toachieve sympathetic denervation of the heart and lung.

Left side. For left sided therapy, in some embodiments, the catheter isintroduced into the femoral vein and advanced up the inferior vena cavato the right and left ascending lumbar veins and on to the right azygosvein and the left hemiazygos vein, respectively. The left hemiazygosvein typically communicates directly with the accessory hemiazygos veinand so catheter access can be gained directly into the accessoryhemiazygos system. In the absence of continuity, the accessoryhemiazygous may be accessed directly off of the azygous vein. Therapycan be delivered from the accessory hemiazygos vein or hemiazygos veindirectly to the targeted paravertebral space(s), particularly in themid- to lower-thoracic levels, as described above. For the lowerthoracic levels, the catheter can be advanced into the left-sidedintercostal veins and therapy delivered to the paravertebral space fromthere. The intercostal vessels on the left side are considerably smallerthan the left above T5. For example, at the third and fourth intercostalspace, over 80 percent of intercostal veins are smaller vessels withonly 10-15% medium and 2-5% large. The majority of these vessels,including the superior intercostal vein, take a posterior path relativethe sympathetic chain. Various embodiments for delivering the therapy tothe left side are described above. Similarly, as fibers cross theaccessory hemiazygous on their way to the plexi of the heart and lungsin a similar fashion to the azygous, these regions may be treated withlinear RF burns.

FIGS. 10A-10C illustrate different anatomical variants in anatomy of theintercostal veins, e.g., the superior intercostal vein 1000 with respectto the left third intercostal ganglion 1004 and nerve 1006. Also shownare the left third rib R3 and left fourth rib R4. FIG. 11A illustrates arelatively small superior intercostal vein 1000 that courses generallyinferior to the left third intercostal nerve 1002; FIG. 11B illustratesa medium-sized superior intercostal vein 1000 that courses generallyinferior to or at the level of the left third intercostal nerve 1002;and FIG. 11C illustrates a relatively large superior intercostal vein1000 that courses at some points superior to the left third intercostalnerve 1002. FIGS. 12A-12C illustrate the respective anatomy of FIGS.11A-11C, with a catheter 110 being deployed into the superiorintercostal vein 1000. FIGS. 13A-13C illustrate the respective anatomyof FIGS. 11A-11C, illustrating expansion of an expandable member 1200(e.g., an inflatable balloon) positioned at the distal end of thecatheter 1100 against the wall of the vessel 1000. A curvable needle1202 sheathed by, or otherwise operably associated with the expandablemember 1200 can deploy a needle across the wall of the vessel 1000, andthe therapeutic agents can be delivered into the desired anatomicallocation (e.g., the paravertebral gutter) as described elsewhere herein.The expandable member can then be contracted (e.g., by deflation of theballoon) and the catheter 1000 removed from the body. FIG. 14Aillustrates schematically a different view of a catheter 1100 with anexpandable member 1200 at its distal tip within a vessel V, such as anintercostal vein for example. Also shown is the sympathetic trunk 701and the paravertebral gutter (500, within dotted lines). FIG. 14Billustrates schematically the expandable member 1200 being expanded(e.g., balloon inflation). FIG. 14C illustrates the curved needle 1202sheathed by or otherwise associated with the expandable member cominginto contact with and extending radially outwardly through the wall ofthe vessel V, and the therapeutic agents can be delivered into theparavertebral gutter 500. The catheter 1000 can then be removed aspreviously described.

Bilateral. If bilateral therapy is desired, the catheter can then beretracted back to the superior vena cava and advanced up to the leftbrachiocephalic vein and then directed caudally in the superiorintercostal vein. From here, therapy can be delivered to the secondthrough the fourth intercostal veins. Occasionally there is a connectionbetween the fourth and fifth intercostal veins, in which case therapycan also optionally be delivered from this route to the fifthintercostal vein. Alternatively, if there is communication between thehemiazygos and the azygos veins, a catheter can be directed from theazygos system, across the communicating vein between the hemiazygos andazygos veins, up the accessory hemiazygos vein and into the intercostalvein system. If therapy to the fifth intercostal vein is also desired,the catheter can then be returned to the azygos vein and advanced acrossthe accessory hemiazygos vein to reach the fifth and sixth intercostalveins. In approximately 15% of individuals, the accessory hemiazygosvein is incompletely formed and in these situations the azygos islocated closer or on the midline. In these patients, the catheter can beadvanced directly from the azygos vein to the intercostal vein. As withthe right side, therapy can be delivered from each of the second to thesixth, such as the second to the fifth, or the second to the fourthintercostal veins to reach the sympathetic chain and surrounding nervesat those respective levels.

In the same manner that the delivery to multiple contiguousparavertebral spaces is achieved on the right side, therapy can bedelivered from one of the 1) superior intercostal vein, 2) the accessoryhemiazygos vein, preferably between the intercostal veins 3) thesuperior intercostal vein 4) the second intercostal vein 5) the thirdintercostal vein, 6) the fourth intercostal vein, 7) the fifthintercostal vein or 8) the T-junction that forms between thecommunicating vein that forms between the communicating vein (fromazygos), the accessory hemiazygos vein and the hemiazygos vein.

The catheter can be advanced along the intercostal veins to the regionbetween the accessory hemiazygos vein (or hemiazygos vein, asappropriate) to at or adjacent to where the sympathetic chain crossesthe intercostal vein.

If venous access to these locations is desired from the right internaljugular vein, the catheter can then be advanced through the rightbrachiocephalic vein to the superior vena cava and then the azygos veinto access the right side as described above. Access to the left side isfrom the right internal jugular vein to the right brachiocephalic veinto the left brachiocephalic vein down to the superior intercostal veinas described above. Occasionally, the supreme/superior intercostal veinson the right and left side drain into the azygos vein directly.

If venous access to the right or left sides is desired from percutaneouspuncture to the right subclavian vein, access is gained to the rightbrachiocephalic vein (right innominate) and then continues to theappropriate location as described above. Similarly, if venous access isdesired from percutaneous puncture to the left subclavian vein, accessis gained to the left brachiocephalic vein (left innominate) and thencontinues to the right or left side as described above. Occasionally,the azygos vein opens into the right brachiocephalic or even the rightsubclavian directly instead of the superior vena cava. Alternatively,the pulmonary veins have been found opening into the azygos vein. Inthese cases, the access route may have to be adjusted accordingly.Percutaneous access can also be made through a radial vein or otherveins of the upper thorax.

In another embodiment, catheter access to the bronchial veins isdesired. These veins can be accessed directly from the azygos vein onthe right side or the left superior intercostal vein or accessoryhemiazygos vein on the left side.

Arterial Access.

As with the venous access, in some embodiments the goal of anendovascular approach is to access the sympathetic chain and adjacentafferent/efferent nerves that innervate the lung at the second throughsixth, most preferably second through fifth, and ideally the secondthrough fourth levels.

The approach to accessing the second thoracic level differs from thethird levels down and is described here. From a right or left femoralartery, a catheter can be advanced up the descending aorta across theaortic arch, through the brachiocephalic trunk (artery) to the rightsubclavian artery, to the costocervical trunk, if present, and down thesuperior (supreme/highest) intercostal artery. This artery providesblood to the stellate and/or T1 ganglia. Alternatively other directunnamed branches from the subclavian, branches from the inferior thyroidartery and ascending cervical arteries also supply blood to the stellateganglion) The right second posterior intercostal artery provides directaccess the second thoracic level on the right side. On the left side,the catheter can then be maneuvered up the descending aorta, across theaortic arch and up through the left subclavian artery to thecostocervical trunk and down the superior (supreme/highest) intercostalartery to the left second posterior intercostal artery. For theremaining thoracic levels three through six, the posterior intercostalarteries can be accessed directly from the descending aorta on the rightand left side. Therapy can be delivered from an intravascular locationin the intercostal vessel immediately adjacent to the sympathetic chainor from the region between the sympathetic chain and the attachment ofthe intercostal artery to the aorta. Ablating along this vessel allowsfor therapy delivery to the afferent and efferent rami that run along tovessel to the heart and lungs. Given that this is an arterial system,the Mercator Bullfrog catheter as described in U.S. Pat. No. 8,708,995to Seward et al., which is hereby incorporated by reference in itsentirety, can be adapted for doing delivery into this space.

Arterial access can also be gained directly from an access point in theright or left radial artery and a catheter advanced from the radial tothe brachial artery to the subclavian artery. Additional advancementfrom the subclavian artery is described above to the second (posterior)intercostal artery as well as the third through sixth intercostalarteries above. In one embodiment, the right and left thoracicsympathetic chain are accessed through the right and left sided arterialaccess points, respectively. In another embodiment, the brachial arteryis accessed instead of the radial artery.

As with the endovascular venous access approach, multi-level therapy maybe achieved to the neural structures within the paravertebral gutterthrough a catheter positioned at one arterial access point, includingbut not limited to one of the following: 1) the second posteriorintercostal artery, 2) the third posterior intercostal artery, 3) thefourth posterior intercostal artery, or the 4) fifth posteriorintercostal artery. An agent or therapy may travel from one intercostallevel to treat multiple adjacent thoracic intercostal levels through thecontinuity provided in the paravertebral space. The agent or therapy canthen be delivered rostrocaudally, rostrally, or caudally to multiplelevels to treat the nerves in the paravertebral gutter. Alternatively,therapy may be delivered directly from the aorta to the paravertebralgutter.

In another embodiment, the catheter is advanced from the descendingaorta to the left bronchial arteries (superior, inferior) directly fromwhere therapy is delivered to the lung hilum on the right and leftsides. On the right side, the right bronchial artery can be approachedfrom the thoracic aorta directly or from a common trunk to the rightthird (posterior) intercostal artery to the right bronchial artery. Theright bronchial artery may also originate from the left superiorbronchial artery or another right intercostal artery. An agent ortherapy may be delivered directly from the bronchial artery to theregion surrounding the bronchial artery. In one embodiment, therapy isdelivered from the posterior bronchial artery that runs with/along tothe posterior pulmonary plexus. In this manner, the nerves in posteriorpulmonary plexus may be targeted.

In another embodiment, the catheter is advanced into the aortic arch andtherapy is delivered to the lower curvature of the arch, from wheretherapy is delivered. This lower curvature is a lower pressure systemthan the upper curvature and thus has less arteriosclerotic plaque. Thelower curvature also is adjacent to the superficial cardiac plexus andthe baro- and chemo-receptors that regulate the cardio-pulmonary system.The lower curvature also allows delivery directly to the nerves enteringon the trachea and right and left primary bronchus.

In another embodiment, the catheter is advanced down the descendingaorta and therapy is delivered circumferentially around the aorta toaddress fibers that are running posteriorly, laterally and anteriorlyaround the great vessel.

In one embodiment, the venous system is accessed to deliver therapy tothe right side and then the arterial system is accessed to delivertherapy to the left side or vice versa.

In another embodiment, therapy is directed towards the renal arteryfirst followed by treatment of the sympathetic chain and/or associatedrami. In yet other embodiments, therapy is directed towards the carotidbody, carotid sinus, the parasympathetic system or more specifically thevagus, prior to or concurrent with treatment in some embodiments.

Direct Intercostal Access to Intercostal Artery or Vein.

As an alternate to above traditional vascular access points, anultrasound probe can be used to guide and introduce a needle andcatheter directly into the intercostal vessels from a more lateralposition relative to the spine. Again, a target level is identified,using the rib/spinous process as a guide, and the access is on theunderside of the target rib. The catheter is advanced along theintercostal artery or vein until it is adjacent to the sympatheticchain, or, approximately 1-2″ from the connection with theazygous/accessory hemiazygous/hemiazygous. An EP catheter can be used toID the sympathetic chain. At this location, an agent or therapy can bedelivered in or around the sympathetic chain or in/around theparavertebral space. Alternatively, the catheter can be advanced moremedially through the intercostal artery or vein to modulate the nervesinnervating the bronchial arteries.

Intraprocedural Monitoring of Sympathetic Activity.

During the procedure, using a standard procedural approach with femoralaccess, coronary sinus recordings with a fixed curve decapolarcatheter/quadriplar catheter can be made to monitor the cardiacsympathetic nerve activity.

Various other modifications, adaptations, and alternative designs are ofcourse possible in light of the above teachings. Therefore, it should beunderstood at this time that within the scope of the appended claims theinvention may be practiced otherwise than as specifically describedherein. It is contemplated that various combinations or subcombinationsof the specific features and aspects of the embodiments disclosed abovemay be made and still fall within one or more of the inventions.Further, the disclosure herein of any particular feature, aspect,method, property, characteristic, quality, attribute, element, or thelike in connection with an embodiment can be used in all otherembodiments set forth herein. Accordingly, it should be understood thatvarious features and aspects of the disclosed embodiments can becombined with or substituted for one another in order to form varyingmodes of the disclosed inventions. Thus, it is intended that the scopeof the present inventions herein disclosed should not be limited by theparticular disclosed embodiments described above. Moreover, while theinvention is susceptible to various modifications, and alternativeforms, specific examples thereof have been shown in the drawings and areherein described in detail. It should be understood, however, that theinvention is not to be limited to the particular forms or methodsdisclosed, but to the contrary, the invention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the various embodiments described and the appended claims.Any methods disclosed herein need not be performed in the order recited.The methods disclosed herein include certain actions taken by apractitioner; however, they can also include any third-party instructionof those actions, either expressly or by implication. For example,actions such as “accessing the paravertebral gutter” includes“instructing the accessing of the paravertebral gutter.” The rangesdisclosed herein also encompass any and all overlap, sub-ranges, andcombinations thereof. Language such as “up to,” “at least,” “greaterthan,” “less than,” “between,” and the like includes the number recited.Numbers preceded by a term such as “approximately”, “about”, and“substantially” as used herein include the recited numbers (e.g., about10%=10%), and also represent an amount close to the stated amount thatstill performs a desired function or achieves a desired result. Forexample, the terms “approximately”, “about”, and “substantially” mayrefer to an amount that is within less than 10% of, within less than 5%of, within less than 1% of, within less than 0.1% of, and within lessthan 0.01% of the stated amount. Furthermore, various theories andpossible mechanisms of actions are discussed herein but are not intendedto be limiting.

What is claimed is:
 1. A method of modulating nerves of a patient,comprising: inserting a catheter percutaneously into a first bloodvessel; advancing the catheter into a second blood vessel; penetrating awall of the second blood vessel with a portion of the catheter, therebyaccessing the paravertebral gutter; and modulating nerves within theparavertebral gutter by delivering a gel comprising a therapeutic agentinto the paravertebral gutter.
 2. The method of claim 1, wherein thesecond blood vessel is selected from the group consisting of: an azygousvein, a hemiazygous vein, an accessory hemiazygous vein, a superiorintercostal vein, an intercostal vein other than the superiorintercostal vein, a costocervical trunk, and a subclavian artery.
 3. Themethod of claim 1, wherein the modulating comprises delivering ahydrogel comprising a therapeutic agent to modulate nerves in theparavertebral space.
 4. The method of claim 3, wherein the hydrogelcomprises an in situ crosslinking hydrogel or an injectable hydrogelslurry.
 5. The method of claim 1, wherein the modulating comprisesreducing the signs or symptoms of asthma or pulmonary hypertension. 6.The method of claim 1, wherein the modulating comprises reducing thesigns or symptoms of cardiogenic pain.
 7. The method of claim 1, whereinthe modulating comprises reducing the signs or symptoms of cardiacarrhythmias.
 8. The method of claim 1, wherein the nerves comprise oneor more of sympathetic visceral efferent, sympathetic peripheralefferent, visceral afferent, somatic afferent and somatic efferent, andwherein the nerves reside proximate the C7 to T5 spinal levels.
 9. Themethod of claim 1, wherein the nerves comprise one or more ofcommunicating rami, the sympathetic ganglia, the sympathetic chain,intermediate or accessory ganglia, the spinal nerve, and the intercostalnerve.
 10. The method of claim 1, further comprising delivering the gelto the dorsal or ventral roots.
 11. The method of claim 1, wherein thegel comprises polyethylene glycol.
 12. The method of claim 1, whereinthe therapeutic agent comprises a neurolytic.
 13. The method of claim 1,wherein the neurolytic reduces the release of norepinephrine.
 14. Themethod of claim 1, wherein the gel comprises polyethylene glycol.
 15. Amethod of selectively modulating nerves of a patient, comprising:inserting a catheter percutaneously into a first blood vessel; advancingthe catheter into a second blood vessel; penetrating a wall of thesecond blood vessel with a portion of the catheter, thereby accessingthe paravertebral gutter of the patient; and protecting a first group ofnerves or neurons within the paravertebral gutter from neurolysis,wherein protecting comprises delivering a first hydrogel into theparavertebral gutter in a first direction; and neuromodulating a firstgroup of nerves or neurons within the paravertebral gutter, whereinneuromodulating comprises delivering a second hydrogel into theparavertebral gutter.
 16. The method of claim 15, wherein the firsthydrogel comprises a neuroprotectant.
 17. The method of claim 15,wherein the first hydrogel is released proximate the first rib towardthe inferior cervical ganglion or the region of the stellate ganglioncomprising the inferior cervical ganglion.
 18. The method of claim 15,wherein the second hydrogel comprises a neurolytic agent.